37747019 opiates 1986 george r lenz suzanne m evans d eric walters anton j hopfinger academic press...

Frontispiece: Potential energy field of morphine at its van der Waalssurface using a proton probe

Opiates

George R. LenzHealth Care Research and

DevelopmentBritish Oxygen Corporation

GroupMurray Hill, New Providence.

New Jersey

Suzanne M. EvansDepartment of Medicinal

Chemistry andPharmacognosy

University of Illinois atChicago

Chicago, Illinois

D. Eric WaltersMolecular Design GroupNutraSweet Research amI

DevelopmentSkokie, Illinois

A. J. HopfingerDepartment of Medicinal

Chemistry andPharmacognosy

University of Illinois atChicago

Chicago. Illinois

With a chapter byDonna L. HammondSection of Central Nervous

System DiseasesG. D. Searle & CompanySkokie, Illinois

1986

~ACADEMIC PRESS, INC.Harcourt Brace Jovanovich, Publishers

Orlando San Diego New York AustinBoston London Sydney Tokyo Toronto

Contents

~PYR[GHT @ [986 BY ACADEMIC PRESS, INC.ALL RIGHTS RESERVED.NO PART OF THIS PUBL[CATION MAY BE REPRODUCED ORTRANSMI1TED [N ANY FORM OR BY ANY MEANS, ELECTRON[COR MECHAN[CAL, INCLUDING PHOTOCOPY, RECORDING, ORANY [NFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUTPERMISS[ON IN WRITING FROM THE PUBLISHER.

Preface ix

ACADEMIC PRESS, INC.Orlando, f10rida 32887 1 Morphine and Its Analogs

I. IntroductionII. The Biosynthesis and Metabolism of Morphine

References

I7

24United Kingdom Edition published by

ACADEMIC PRESS INC. (LONDON) LTD.24-28 Oval Road, London NWI 7DX

LIBRARY OF CONCRESS CATALOCING-iN-PUBLICATION DATA:2 Biological Effects of Opioids

(by Donna L. Hammond)Main entry under title:

[ncludes index.]. 'LNarcolics.-Models. 2. Narcotics-Structure-

activity relationships. 3. Chemistry, Pharmaceutical.I. Lenz, George R. IDNLM: I. Narcotics. QV 89 06131RS431.N370/i5 1986 615'.7822 85.1997:i[SBN 0-12-443830.X (alk. paper)

I.II.

III.IV.V.

VI.VII.

IntroductionMultiplicity of Opiate ReceptorsAnalgesiaRespiratory DepressionGastrointestinal MotilityDependence LiabilitySummaryReferences

2931353738394041

Opiates. .

PRINTED IN THE UNITED STATES OF AMERICA

3 Synthesis and Structure-Activity Relationships

of Morphine, Codeine, and Related Alkaloids

I. Syntheses of Morphine, Codeine, and Related Alkaloids 45II. The Structure-Activity Relationships of Morphine and Related

Compounds 55III. Diels-Alder Adducts of Thebaine 101IV. The Chemical Anatomy of Morphine and Its Derivatives 155

References 15786871!81!9 987654321

\I

vi Contents Contents vii

4 Physical Chemistry, Molecular Modeling, andIII. Molecular Modeling and Quantitative Structure-Activity

Relationship (QSAR) Studies 388QSAR Analysis of the Morphine, Morphinan, References 398and Benzomorphan Analgesics

I. Physicochemical Studies 166 9 Open-Chain AnalgesicsII. Molecular Modeling and QSAR Studies 174 I. Methadone and Related Compounds

References 185 400II. Other Open-Chain Compounds 435

References 445

5 The Morphinans

I. Introduction 188 10 Physical Chemistry and Molecular ModelingII. Naturally Occurring Morphinans 189 of Open-Chain Analgesics

III. Conversion of Morphine and Its Analogs to Morphinans 190IV. The Total Synthesis of Morphinans 193 I. Physical Chemistry Studies of Open-Chain Analgesics 448

V. Structure-Activity Relationships of the Morphinans 206 II. Molecular Modeling of Open-Chain Analgesics 456

VI. The Chemical Anatomy of the Morphinans 242 References 457

References 243

11 Enkephalins6 The Benzomorphans I. Introduction 459

I. Introduction 250 II. Opioid Peptide Precursors 463

II. Benzomorphan Syntheses 252 III. Peptide Synthesis 471

III. Structure-Activity Relationships in the Benzomorphan IV. Enkephalin Selectivities for the J1.and 0 Opiate Receptors 473

Analgesics 259 V. Minimum Enkephalin Chain Length Necessary for Analgesia 48]

IV. The Chemical Anatomy of the Benzomorphans 310 VI. Structure-Activity Relationships in the Enkephalins 482

References 311 VII. Clinically Investigated Enkephalin Analgesics 500VIII. The Chemical Anatomy of the Enkephalins 502

References 5037 Piperidine Analgesics

I. Introduction 318 12 Physical Chemistry and Molecular ModelingII. Meperidine Family 319 of the Enkephalins

III. Bemidone Family 331IV. Prodine Family 334 I. Introduction 513V. Alkyl Family 352 II. Solid-State Conformations 514

VI. Anilino Family 362 III. Solution Conformations 516References 367 IV. Molecular Modeling Studies 532

V. QSAR Studies 537

8 Physical Chemistry, Molecular Modeling,References 537

and QSAR Analysis of the Arylpiperidine index 543Analgesics

I. Physicochemical Studies 377II. Stereostructure, Conformation, and Biological Activity 385

Preface

Research in the pharmaceutical sciences is becoming increasingly inter-disciplinary. The days of organic and medicinal chemists and pharmacolo-gists being the only members of the preclinical research team are gone.The trend in research is to study chemical and biological events on themolecular level as well as to work in the more traditional domain ofanimal pharmacology. This has resulted in the addition of new membersto the research team. Experts in molecular spectroscopy and physicalchemistry are aiding in the interpretation of structure-activity data. Inmany cases the biology is divided up among animal pharmacologists,molecular pharmacologists, biochemists, and molecular biologists. Thenewest member of the research team, the "drug designer," uses the com-puter to establish predictive criteria relating the physicochemical proper-ties of molecules to their observed biological endpoints.

Unfortunately, preclinical research monographs in the pharmaceuticalsciences are not usually coauthored by all members of today's preclinicalresearch team. Generally, the result is a discussion deep in some topicsand shallow in others. Further, the integration and continuity of the com-ponent topics are often fragmented and incomplete. Often the reader isforced to scan through a set of reference books to assemble a comprehen-sive overview.

We believe that a unique aspect to this book on the opiates is thatexperts in each of the major components-synthetic chemistry, medicinalchemistry, pharmacology, physical chemistry, and drug design-haveteamed together to generate a complete text. Thus the discussion of theopiates is uniformly complete and integrated across all subdisciplines.

The structure of the chapters reflects the inclusion of detailed reviewsof each of the various subdisciplines. Discussions of organic synthesesand reporting of structure-activity relationships predominate throughoutthe book, reflecting our greater knowledge of certain topics than ofothers. The book is organized around simplification of the rigid molecularframework inherent in morphine. Chapter I describes the history, biosyn-thesis, and metabolism of the naturally occurring morphine. A special

ix

x Preface

effort has been made in Chapter 3 to put together a complete, but alsoconcise, summary of the enormous amount of work done on morphine,codeine, and related alkaloids. Cleaving the dihydrofuran ring in mor-phine yields the analgesic morphinans (Chapter 5). Continuing simplifica-tion by scission of the C-ring in the morphinans forms the benzomorphans(Chapter 6), an area of continuing research interest. Further bond break-ing leads to the arylpiperidines (Chapter 7), where analgesics as potent asthe thebaine Diels-Alder adducts have been observed. The seeminglyultimate simplification results in the open-chain analgesics (Chapter 9),where an aromatic ring is joined to an amino by a flexible chain. Chapter11 describes the endogenous ligands for the opiate receptors, theenkephalins, and the biosynthesis and SAR investigations into this fasci-nating class of peptide analgesics. It is interesting that out of the thou-sands of enkephalin analogs prepared, only three have made it to clinicalinvestigation and these seem to have undesirable clinical profiles. InChapter 2, Donna Hammond contributes an invited discussion on thebiological effects of opioids. The style of this chapter is such that it iseasily read by a synthetic chemist who has a minimal background inopioid biology. The discussions (Chapters 4, 8, 10, and 12) of the physicalchemistry, molecular modeling, and QSAR investigations of the variousclasses of opioids following the medicinal chemistry chapters are uniqueentries to a treatise in this field.

The book leaves several major questions unanswered. Such is to beexpected from a text on a dynamic research field. It is the nature of thebeast. Nevertheless, we collectively wish that we could provide moreinsight into, for example, the active conformation and shape of theenkephalins, the common three-dimensional pharmacophore among opi-ates, and the physicochemical properties governing opiate receptor speci-ficity. Nevertheless, we feel that the most current information on theseand other pressing questions is provided to the reader.

Lastly, many people besides ourselves are responsible for this bookbecoming a reality. Professor H. A. Scheraga of Cornell University firstsuggested to one of us, AJH, the need for a book of this type. At that timeall four of us were members of Research and Development at G. D. Searle& Co. of Skokie, Illinois. Interestingly, as this book goes to press, none ofus is now a member of Searle R & D. While senior R & D management atSearle did not go out of the way to encourage us on this project, they alsodid not discourage us and allowed us to use company clerical services togenerate a working manuscript.

A number of people at Searle helped in the preparation of themanuscript. However, Ms. Sue Christain was of key importance ingenerating both text and structures. She is our silent, fifth author. Other

Preface xi

Searle personnel who unselfishly gave us their time and skills are Ms.Grace Koek, Ms. Dolores Weiman, and Ms. Linda Tepper.

This has been a long and arduous project for all of us. However, it is anundertaking that will provide a common bond to sustain our friendship foryears to corne.

J'GEORGE R. LENZ

SUZANNE M. EVANS

D. ERIC WALTERS

A. J. HOPFINGER

1.Morphine and Its Analogs

J. IntroductionA. History.B. Occurrence .C. Production and Use . . .. .

II. The Biosynthesis and Metaholism of MorphineA. MorphineBiosynthesis . . . . . . . .. . ...B. Morphine Alkaloid Biotransformation in Animal SpeciesC. Biotransformation in Papaver SpeciesD. Morphine DispositionReferences . . . . .

II2577

13192024

I. Introduction

A. History

The development of the first effective analgesic drug, opium, was almostcertainly accidental and occurred in prehistory. When the unripe seedcapsule of the opium poppy, Papaver somniferum L., is incised, a viscousmilky fluid is exuded. As this exudate is exposed to air, it dries and darkensto a hard, slightly sticky mass known as opium. The potent biologicaleffects of opium were recognized in ancient times, and for many milleniathis substance has been used by the practicing physician. Its sedative andeuphoric properties have also caused opium to have a long folklorichistory. The ancient Egyptians knew of its properties, and it has beenvariously smoked or eaten and ingested as its alcoholic tincture, laudanum.It has found use as a poison (1), but its major use has been for the reliefof pain. Morphine, the major active ingredient of opium, is used today asan analgesic in controlling severe pain despite the development ofmore potent and efficacius opiates. The intense development of analgesicson the basis of the morphine framework might not have occurred as readilywere it not for the numerous other biological activities inherent in themorphine molecule. Deleterious side effects include respiratory depres-sion, constipation, and marked sedation. Morphine also acts as a eupho-riant while at the same time causing addiction. These last effects, coupledwith the tolerance that develops to it, make morphine a readily abusablesubstance (2). The separation of the analgesic effect from the others hasoccupied medicinal chemists for many decades.

2 1 Morphine and Its AnalogsIntroduction

Although opium contains a variety of alkaloids, its major. constituentand the most potent analgesic is morphine (1) (3). MorphIne has thedistinction of being the first nitrogenous base to be isolated from a livingsource and is one of the most intensively investigated and intriguingmaterials in the history of chemistry (4). The isolation of an opiumconstituent in crystalline form was first achieved in 1803 by Derosne, anapothecary living in Paris (5). He ~iluted a syrupy extract of opium withwater and precipitated the salt of opIUm wIth potassIUm carbonate. SeguIn,in 1804, presented a paper to the Institute of France entitled "Sur I'opium," in which he described the isolation of morphine from opi~m (6).Morphine was isolated as a crystalline substance In 1806 by FnednchWilhelm Sertiirner, an apothecary, in the city of Paderborn in theKingdom of Hanover (7). It is Sertiirner who is usually credited with the.discovery and isolation of morphine. Johann Bartholomaus Trommsdorff,editor of Trommsdorff's Journal of Pharmacy, where Sertiirner's workappeared, was moved to remark (8):

Dee Versuch def herm Prof. enthalten manche sehr interreste Ansichten, wofOr ihm

das chemische Publikum viel dank schuldig ist. So vielfach aber nun 3uch die Arbeiten

iiber das Opium sind, so darf Man die Asten noch kleineswegs als geschloBen ansehen,

uDd es ist vielmehr zu wunschen, das dieser Gegenstand ooeh weiter untersucht

werden moehte, urn manche ooeh obwaltenende Dunkelheiten in ein helleres Licht zu

setzeD. Vorzuglich wiinschte leh, das die Versuche mit etwas groBen Mengen mochternwiederholt werden.

As a result of this entreaty, suppliers in various obscure corners of the NearEast and Far East hastened to comply with this dictum, and have suppliedincreasing amounts of morphine and its derivatives ever since.

The scientists involved in the study of morphine read like a Who's Whoof nineteenth-century chemistry: Liebig, Knorr, Wieland, Pschorr,Gadamer, and many others. Despite the plethora of experimental <;>bserva-tions, the correct structure for morphine (1) was not postulated until 1925by Sir Robert Robertson (9). The absolute configuration was not deter-mined until the mid-1950s (10), shortly before the total synthesis ofmorphine was reported, over 150 years after its isolation (lla).

Table I-I

Alkaloids Found in Opium a

)

6-Acetonyldihydrosanguinarine{3-Allocryptopine

BerberineCanadineCodamineCodeine (0.5%)Codeine N-oxidesCodeinoneCoptisineCoreximine

Corytuberine

Cryptopine

Dihydroprotopine

Dihydrosanguinarine

GlaucineGnoscopineHydrocotarnine

10-H ydroxycodeine16-Hydroxythebaine(+ )-Isoboldine(- )-Isocorypalmine

Lanthopine

LaudanidineLaudanineLaudanosineMagnoflorine

6-Methylcodeine

N-Methyl-14-0-desmethylepiporphyroxineMorphine (10-20%)

Morphine N-oxides

Narceine (0.2%)Narceine imide

NarcotineNarcotoline

NeopineNormorphine

Nornarceine

Norsanguinarine

Orientaline

13-0xocryptopine

Oxydimorphine

Oxysanguinarine

PacodinePalaudine

Papaveraldine

Papaveramine

Papaverine (1%)

Papaverrubine C

Porphyroxine

ProtopinePseudomorphine

(z)- Reticuline

Salutaridine

Salutaridinol-I

Sanguinarine(

- )-Scoulerine

Stepholidine

Tetrahydropapaverine

Thebaine (0.3%)

Thebaine N-oxides

a From Santavy (11b,llc).

B. Occurrence

The opium derived from Papaver somniferum contains at least 50alkaloids, with the major constituent being morphine. The alkaloidscontained and the percentage of occurrence of the major alkaloids arepresented in Table I-I. The opium alkaloids are derived biogeneticallyfrom I-benzylisoquinolines, which, in turn, are derived ultimately fromphenylalanine. The more complicated alkaloids, with regard to theirtherapeutic uses, can be classified structurally either as (a) those con-taining a reduced benzylisoquinoline group in the form of a hydrophen-

anthrene nucleus or (b) those containing an intact, albeit modified,benzylisoquinoline nucleus. The most important hydrophenanthrene-based alkaloids are morphine (I), codeine (2), and thebaine (3). Benzyliso-quinoline-based alkaloids are exemplified by papaverine (4) and dl-narcotine (5).

Despite their common precursor, it is perhaps not surprising that thehydrophenanthrene and the other benzylisoquinoline alkaloids have radi-cally different biological profiles. The phthalideisoquinoline alkaloid dl-narcotine (5) is used primarily as an antitussive, while the closely relatedbicuculline is a potent antagonist of the central nervous system (CNS)neurotransmitter y-aminobutyric acid. Papaverine (4) is a smooth musclerelaxant with little CNS activity. Codeine (2), a centrally acting analgesic,

4 1 Morphine and Its Analogs I Introduction 5

o

although weaker than morphine, is characterized by its oral activity and isused extensively as an antitussive. Thebaine (3), on the other hand, is verytoxic and produces strychnine-like convulsions. Thebaine is in demand,however, as an intermediate for the preparation of the highly potent14-hydroxymorphinan derivatives and as a point of entry for the synthesisof compounds derived from Diels-Alder additions to its cyclic dienesystem. In contrast to its low content in the opium poppy, it is the mainalkaloid in another species of poppy, Papaver bracteatum, which does notcontain morphine (12). Although thebaine is readily' convertible tocodeine, it has to be subsequently de methylated to produce morphine.One means of reducing illegal opium traffic would be to curtail thecultivation of the opium poppy, P. somniferum. This would restrict theavailability of alkaloid raw material that is readily convertible to heroin(diacetylmorphine) while allowing the cultivation of P. bracteatum in orderto extract thebaine and convert it to pharmaceutically acceptable products.See Gordon's review (2) for an account of the economics of manufacture ofand illicit dealings in opium.

C. Production and Use

Although opium's most famous alkaloid is morphine, the most widelyutilized drug for the relief of mild to moderate pain and as a coughsuppressant is codeine (2). Codeine accounts for about 90% of U.S.consumption of opium derivatives (13). The majority of opium availablefor export in the global market comes from India and, to a lesser extent,Turkey. The Soviet Union, which has a significant opium-producingcapacity, consumes most of its production. The global and U.S. consump-tion of codeine from 1970 to 1974 and the projections from 1975 on areshown in Table 1-2. As the. table shows, in contrast to relatively stableglobal consumption, the United States had an average increase of over10% per year in the reported period. In the preceding decade, consump-tion was relatively stable.

A crisis occurred in 1972-1973 that threatened to produce a shortage ofopium in the United States. This crisis was due to a number of factors: (a)partial crop failures in India substantially reducing the raw opium supplies,(b) a total ban on opium poppy growth, starting in 1973, by the Turkishgovernment under U.S. government pressure, and (c) the Soviet Unionbecoming a net importer of opium for the first time. Because of thethreatened shortage at the consumer level, the U.S. government wasforced to release portions of its strategic stockpile reserves of opium todomestic producers in order to meet domestic requirements.

This crisis forced both U.S. and international assessment of the requiredamounts and suppliers of codeine. It also stimulated interest in the

Morphine

~O OR

2 Codeine 4 Papaverine

3 Thebaine 5 dJ-NarcotineOCR)

Scheme }./. Derivation of the reduced and nonreduced benzylisoquinolines from acommon precursor.

6

Table 1-2

1 Morphine and Its Analogs

Year Worldwide (metric tons)

Codeine Consumption in the United States and Worldwide"

United States (metric tons)

19701971197219731974197519781980

158150156163155166"177"186"

2326.528.53334.937.5"45"50.1 h

{I

From Schwartz (/3).h Projections.

Table 1-3

U.S. Drug Enforcement Administration AnalgesicProduction Quotas for 1985

Basic Class (Schedule II) Proposed 1985 Quota

AlphaprodincCodeine (for sale)Codeine (for conversion)DextropropoxypheneDihydrocodeincDiphcnoxylateFentanyl

"ydrocodone

HydromorphoneLevorphanolMeperidineMethadoneMix~d Alkaloids of OpiumMorphine (for sale)Morphine (for conversion)Opium (tinctures, extracts)"Oxycodone (for sale)Oxycodone (for conversion)OxymorphoneSufenlanilThebaine

37.300"54.051,000

3,534.00075,795,000

1,341,000550,000

3,5001,459.(kJO

164,lk~)21,750

7, 999 ,I~k)

1,383,IXkJ22,300

1,142,00)58,084.0002,068,0001,966,000

6.41JO5,00)

5006.890,IJOO

" Grams of anhydrous base.b Grams of powdered opium.

jII The Biosynthesis and Metabolism of Morphine 7

practical production of opium derivatives by total synthesis. The Turkishban on opium poppy crops was rescinded, and alternative sources ofcodeine were investigaled. The most important result was the intensiveinvestigation of thebaine (3), derived from P. bracteatum. The dried latexfrom this poppy contains up 10 55% thebaine (14), which is readilyconvertible into codeine while avoiding morphine as an intermediate. Thisspecies of poppy has the potential to be a commercial crop in the UnitedStates. However, commercial production of P. bracteatum has not beenallowed by the federal government, in part due to political considerationsconcerning the anticipated loss of foreign exchange to the less developed(LDC) producing countries, India and Turkey. Additionally, there issubstantial non medicinal economic usage of Papaver species in the LDCareas (15). The poppy nevertheless retains a potential domestic replace-ment for foreign sources.

Each year the U.S. Drug Enforcement Administration sets aggregateproduction quolas for schedule I and II controlled substances. Thisinformation is published at the end of the preceding year in the FederalRegister. The aggregate production quotas for 1985 in grams of anhydrousbase for the various analgesics are presented in Table 1-3,

II. The Biosynthesis and Metabolism of Morphine

A. Morphine Biosynthesis

The biosynthetic sequence for morphine (1), the major alkaloid of theopium poppy, Papaver somniferum, has been validated through the radio-tracer work of various groups, following a significant structural suggestionmade by Gulland and Robinson in 1925 (9). The el~boration of the laterstages of biogenesis considered the structural resemblance of the morphineskeleton to an unsubstituted 1-benzylisoquinoline (6) which can be ob.tained by breaking bonds A and B. Conversely, a benzylisoquinoline can

CH3 CH3I IN N

~ ,I

0... B OH /'- --1 Morphine 6 7 Laudanine

HDOPA

o~i CO2"

HOHO

11 Tyrosine/HO

13CO2"

HO

12

HO

HO H

<---HO

8 I Morphine and Its Analogs II The Biosynthesis and Metabolism of Morphine

serve as precursor to the aporphine skeleton by another type of ringclosure. In fact, Robinson suggested that laudanine (7) might be abiosynthetic precursor to morphine and its relatives (16).

Thus, early work defined how norlaudanosoline (16), the first 1-benzylisoquinoline recognized along the pathway, was elaborated intomorphine via the key intermediates salutaridine (20) and thebaine (22).Recent work on the early stages of morphine alkaloid biosynthesis hasfocused on the formation of the benzylisoquinoline system itself inattempts to identify the species forming the two halves of the molecule,whose origin is the naturally occurring amino acid tyrosine.

The biosynthesis of morphine (llb,c,17a-j) proceeds along the pathwayshown in Schemes 1-2 and 1-3. Two molecules of the amino acid tyrosine (II)(18) form the basic I-benzyltetrahydroisoquinoline skeleton, with dopamine(10) serving to elaborate one half (19) of this skeleton, ring A with theethylamine side chain. A L-dopa decarboxylase, isolated in Papaver orientale(20) latex, can effect the necessary decarboxylation of dopa to givedopamine.Dopa, the transamination product of 13, however, is incorporated into onlyone C-6-C-2 unit of the key intermediate (14) and the eventual productreticuline (18), whereas tyrosine, which occurs naturally in P. somniferum,via 4-hydroxyphenylpyruvic acid (12) and 3,4-dihydroxyphenylpyruvic acid(B), is incorporated into both C-6-C-2 units, the phenethylamine andbenzylic portions (21). However, the C-l oftyrosine is specifically the sourceofthe carboxyl group in the key intermediate, norlaudanosoline-l-carboxylicacid (14) (22). Decarboxylation of 14 gives the dihydroisoquinoline (15),a known precursor of morphine (23) and the immediate precursor ofnorlaudanosoline (16) (24) in the Papaver species. Confirmation of thispathway has been demonstrated not only in P. somniferum plants andP. orientale seedlings and latex (25), but also in cell-free systems ofP. somniferum stems, seed capsules, and other plant parts, wherein theintermediates 14, IS, and 16 have been formed from dopamine and3,4-dihydroxyphenylpyruvic acid (26). Dihydroxylation of both aromatichalves is necessary before joining to give 14, as shown by the fact that theintermediate (25) is a poor precursor for morphine (25).

9

14

I

<---

17(+)-Norlaudanosoline-dimethyl ether

'\

16 15(~)-Norlaudanosoline

18 OH(~) -Reticuline

Scheme ].2. Norlaudanosoline biosynthesis from tyrosine precursors.

HO

25

10

18 (!-Reticuline) 20 (+)-Salutaridine

1 i

19 23 Neopinone

/

- 2 Codeine


21 Salutaridinol I

1

22 Thebaine

1 Morphine

24 Codeinone

Scheme 1-3. Morphine biosynthesis from norlaudanosoline.

Conversion of norlaudanosoline to reticuline (27) involves both N- anda-methylation. Feeding incorporation studies have shown that 0-methylation, with no selectivity for position, precedes N-methylation,giving (:t)-norlaudanosoline dimethyl ether (17) from (:t)-norlaudanosoline (16). N-Methylation as the terminal step results in(:t )-reticuline (18). In all cases, the methyl group is invariably derivedfrom the S-methyl of methionine and plays an important role in thefurther elaboration of the opiate alkaloids.

Both isomers of reticuline (28), (+ )-reticuline and (- )-reticuline, havebeen found to be incorporated into the morphine alkaloids, with a loss oftritium from C-I of the (+ i-isomer, supporting the conclusion that a rapidequilibration (reversible oxidation-reduction) occurs through the 1,2-

j II The Biosynthesis and Metabolism of Morphine II

IIo20

Salutaridine

18Reticuline

26Diradical(ertha-para)

22Thebaine

21Salutaridinol I

Scheme }.4. Conversion of reticuline to thebaine.

dihydroreticuline intermediate (19) (29). This racemization is enzymic andsubstrate specific, with the evidence for 19 being confirmed by observa-tion. (:t )-Reticuline has indeed been isolated from opIUm, provldmgevidence that the racemate is a naturally occurnng alkalOId (30). In fact,(+ )-reticuline exists in excess in mature poppies ~f P. somniferu.m,however the ( - i-isomer is drawn from the interconvertmg set. ConversIOnof (- )-reticuline to the dienone salutaridine (20) (31), a~ shown m Scheme1-4, occurs directly by an oxidative coupling (32) [the dlradlcal (26) bemgformed from oxidation of the two phenolic hydroxyl groups] as postulatedby Barton and Cohen for phenols (33). One additional ri?gclosure neededto give thebaine (22), the first hydrophenanthrene alkalOId m the pathway,is then accomplished by loss of water from the mtermedIate alcoholsalutaridinoll (21) (34), whose hydroxyl group is on the same side of thering system as the C-15-C-16 bridge. The other isomer wIth oppositestereochemistry at C-7, salutaridinollJ, does not serve as a precursor forthebaine, thus showing the spatial arrangement of the phenohc hydroxyand allylic alcohol necessary for ring closure.

Biotransformation of thebaine to codeine (2) (35), then, occurs throughtwo intermediate ketones, neopinone (23) and codeinone (24) (36), byinitial conversion of the enol ether, not by reduction of thebaine to codeine


oxygenase

[0]

22 Thebaine

1

1

27 Oripavine 23 Neopinone

1

Further biosynthesis

Scheme 1-5. Conversion of thebaine to morphine alkaloids.

methyl ether. Precursor feeding studies in P. somniferum using labeledthebame have shown that this enol ether cleavage involves the loss of the6-0-.methyl group with retention of the 6-oxygen, as shown in Scheme 1-5,possIbly thro~gh a mechanism involving an oxygenase (37), as is known inother aromatIc ether cleavages. In species such as P. bracteatum and P.orientale, whi~h lack enzymes for this C-6 demethylation, biosynthesisstops a~ thebame and branches to oripavine (27) by demethylation of thephenohc ether at C-3 (38).

Migration of the double bond into conjugation produces codeinone (24)from neopmone (23). Codeinone is then reduced to codeine (2), with boththe addItIon and removal of hydrogen at C-7 in the later two steps beingnonspecIfic. O-DemethylatJOn then occurs to give morphine (1) (39).

II

II The Biosynthesis and Metabolism of Morphine t3

Thus, in the later irreversible sequence of steps, two O-demethylations(40) are crucial to the biotransformation of thebaine to morphine.

Also crucial to the biosynthetic pathway are the specific methylatingsteps (41). In the sequence from reticuline to thebaine, the methylation ofparticular hydroxyl groups is critical for directing cyclization, by providinga means of protecting and thereby inactivating phenolic groups in a specificmanner. N-Methylation is helpful for the oxidative coupling (42) step; thelocation of the methoxyls on the rings, however, determines the sites forcoupling. Complete methylation, as in tetrahydropapaverine (28), pre-vents this essential coupling. Differences in methylating systems may thus

CH30

28 Tetrahydropapaverine

account for the fact that various plant species show differing patterns ofalkaloid biosynthesis. Evidence for this is found in the Papaver species P.bracteatum, where a lack of de methylating and hydrogenating capabilitiesresults in thebaine being the final product of opiate alkaloid biosynthesis,with no conversion of thebaine to codeine and morphine (39).

B. Morphine Alkaloid Biotransformation in Animal Species

The biotransformation (43) of morphine, codeine, and heroin has beenstudied in vivo in humans as well as in various animal species, namely, therat, guinea pig, rabbit, cat, and dog. Morphine and codeine typicallyundergo alkylation, dealkylation, and oxidation reactions (heroin, inaddition, undergoes hydrolysis), followed by conjugation prior to elimina-tion. In vitro studies by incubation with isolated enzyme preparations (ratliver and brain, guinea pig liver) have further substantiated the formationof these metabolites. Their importance lies in the biological consequencesof analgesia, with biotransformation being the key determinant of drugonset, duration of activity, and potency.

The major metabolic pathways for morphine (I), codeine (2), and heroin(29), although relatively species dependent for quantitation, are shown in

14 1 Morphine and Its AnalogsII The Biosynthesis and Metabolism of Morphine 1\

0" ~"o

HO'C~HO

OH

H

morphine conjugates generally accounts for 55-65% of the administereddose. The major metabolite in humans, rats, and dogs (45), formed bythe conjugation of morphine with glucuronic acid mainly in the liver, andto a lesser extent in the intestine, kidney, and placenta, is morphine-3-glucuronide (31) (46), shown to be zwitterionic (pKa values = 3.2, 8.1)(47). Morphine-6-glucuronide (32) and the 3,6-glucuronide form in verysmall amounts in humans (totaling only 1% of the 3-glucuronide) (46a);however, they have been easily identified in other mammalian species.Although the 3-glucuronide is much less active than morphine, the6-glucuronide produces a 37-fold increase in analgesic activity and has aprolonged duration compared to morphine sulfate (48). In fact, mostmanipulations of functionality at the C-6 position of morphine havegenerated compounds displaying greater analgesic potency than morphineitself. In the reverse reaction, the glucuronide conjugate at position-3hydrolyzes more readily than that at position-6.

Morphine-3-sulfate (MES) (33), the major conjugate and urinarymetabolite in cats and chickens due to a deficiency of glucuronyl trans-ferase, is the second major metabolite in humans, being formed in a ratioto morphine-3-glucuronide of I: 4 and accounting for 5-10% of anadministered dose (49). This biotransformation again occurs in the liver,the source of the sulfate group thought to be the active intermediateadenosine-3' -phosphate-5-pyrophosphate sulfate, transferred to the phe-nolic hydroxy by a mechanism analogous to the formation of sulfatedmetabolites of hydroxylated steroids (50).

Other reported metabolites occur in such small quantities in most speciesthat they generally do not contribute appreciably to the pharmacologicalactivities observed for morphine, even if they do possess intrinsic agonistopiate-like analgesic properties. An exception to this generalization occursfor metabolism at the key target sites of brain regions having opiatereceptors (99). The enzyme N-demethylase (51), which catalyzes theoxidation of the methyl group to an alcohol and then to an aldehyde, has asits end product normorphine (34) (52), which accounts for 3-5% of anadministered dose (53). Reconversion to morphine has been demonstratedboth in vitro and in vivo in rats (54). The methyl donor is believed to beS-adenosyl-L-methionine, as in O-methylation reactions. Studies haveshown that norcodeine (35), in addition to normorphine (55), and beingformed either from normorphine directly or from codeine itself, is formedin humans (56) and rats (57a). The mechanism (58) again is N-dealkylationby microsomal oxidation in hepatic endoplasmic reticulum (P-450 mixedfunction oxidase) and brain tissue, but its maximal rate does not correlatesimply with the lipophilicity of the substrate (59). These N-dealkylasesin the liver and brain are different in that the brain enzyme shows high

H

,fl.I.,

0"

R''''H 34R':CH.35

R'O 0" ''0

R':H 38

Ft'''CH. 39

A'O 0'-

R'''H 36R'''CH,37

Scheme 1~6. Major metabolic pathways of morphine alkaloids. Key' (a) h d I' bN-

ddea~kYlatlOn. (c) conjugation, (d) O-dealkylation, (e) Q-alkylation' (I ) O:i~~tr~~'

«g

»

re uctton.'

,

Scheme 1-6 (44). Thus, morphine forms metabolites primarily by:

I. conjugation: glucuronidation (43b) at C-3 and C-62. conJugatIOn: ethereal sulfate formation at C-33. N-demethylationjN-oxidation4. O-methylation and O-demethylation

boConjugation, the ~ost common form of detoxification, encompassesth the glucuromdatlOn and sulfate formation reactions. Glucuronidation

usually. serves as the major biotransformation pathway for compoundscontammg a phenolic or alcoholic hydroxyl group and produces a water-soluble compound that is then excreted easily in bile or urine. The sum of

Compound Rl R2 R3

42 8 H 08

43 8 08 8

44 C83 8 08

45 CH3 08 H

Scheme ]-7. C-6 metabolites of hydromorphone and hydrocodone.

16 1 Morphine and Its Analogs

stereoselectivity and displays specificity for agonists. Here, metabo-lism is essential for the expression of morphine's opiate activity sincegreater biological efficacy is attained with increased N-demethylation ofmorphine. Pure narcotic antagonists are not metabolized to the nor-compounds in the brain, although they are effectively so transformed in theliver (99). Thus, contrary to early reports, humans do form nor-compounds as metabolites, even though in only small quantities. Bothnormorphine and norcodeine have been shown to be equiactive inanalgesic receptor. binding affinity compared to their parents (guinea pigileum) (60), although these are exceptions to the generally observedphenomenon of reduced agonist activity on N-dealkylation (61). In variousother morphine derivatives, the N-methyl group has been shown to beimportant for agonism in vitro, the effect being more striking in vivo(mice).

N-Oxide formation of morphine (MNO) (36) and codeine (CNO) (37),catalyzed by amine oxidase (51), is an alternative oxidation biotransforma-tion in guinea pigs and humans. It gives products of undeterminedstereochemistry that arise from oxidation of the tertiary amine, which iscatalyzed by amine oxidase in the liver. MNO has weak analgesic activity,bemg only one-tenth as potent as morphine. Although it has been shown tobe a normal metabolite of morphine, once it is formed (in amounts lessthan 2% of free morphine), its only metabolic pathway in vivo has beendemonstrated in rats to be reduction back to morphine, a reaction thatmay not involve the liver microsomal system. Thus, this metabolic processis reversible, producing as a metabolite of MNO morphine itself, which isactually thought to be responsible for the observed activity of MNO (62).

The ~xidation product hydromorphone [dihydromorphinone (38)], athIrd oXIdatIOn product, has been reported as a metabolite in rats, guineapigS, ~abbits, monkeys, and morphine-dependent humans (46a,53,55).ThIs bIOtransformatIOn accounts for 4% of a dose given to rats and 6-7%of a dose given to monkeys (52d). Hydromorphone itself is a potentnarcotic analgesic (both orally and parenterally, with a potency greaterthan that of morphine) whose metabolic profile (Scheme 1-7) includes C-6reduced a- and/or I3-hydroxy metabolites, with the later formation beingfavored in all species studied, including humans (63). However, a- andf3-dihydromorphine (42, 43) are only approximately one-fifth to two-thirdsas p~tent as hydromorphone, their contribution to the pharmacologicalactIVIty of the morphine parent thus being negligible (potency:hydromorphone > 6a-OH > 6f3-0H metabolite).

Morphine has been shown to undergo O-methylation (64) to codeine inhumans, as well as in rats (53) and dogs, via S-adenosyl-L-methioninemethyl group transfer. Codeine and its metabolites are thought to account

IiII The Biosynthesis and Metabolism of Morphine 17

for up to 10% of an administered dose (65). O-dealkylation regeneratesmorphine. Hydrocodone (39), formed by C-6 oxidation and reductIOn ofthe 7,8-double bond in codeine (humans, guinea pigs, dogs), is a morepotent analgesic then codeine itself. Its greater bioavailability and ~oreextensive O-demethylation to hydromorphone, combmed with ItS mabllltyto form C-6 conjugates, are thought to be responsible for its greater potency.Changes in the oxidation state of the functional group at C-6 of hydroco-done, however, produce metabolites with only a minimal contribu~ion tothe observed analgesic activity. As with morphine, the greatest activity hesin the 6-keto compound, followed by the 6-hydroxy epimers (Scheme 1-7),with the 6a- (44) having only one-seventh the potency of the 613- (45) (57).All three oxidized metabolites nonetheless have a potency greater thanthat of codeine itself.

The major metabolic pathways for the opiate analgesics account for75-85% of an administered dose. The remaining percentage (51) mcludesextremely small amounts of conjugation, oxidation, and reduction products.These are a- and f3-dihydromorphine (51,66) (guinea pig) synthesized byreduction of the ketone in hydromorphone or the 7,8-double bond inmorphine, a- and y-isomorphines (guinea pig, rat, dog, rabbit, humans),hydroxylated morphines, and all of their metabolites. These products,

R

Compound Rl R2

49 allyl OB

50 allyl U

51 cyclopropylmethylene OB

52 cyclopropylmethylene B


however, do not contribute significantly to the observed pharmacologicalprofile of the parent compound or the major metabolites (67).

Heroin [Scheme 1-6 (29)], 3,6-diacetylmorphine, in addition to theabove metabolic pathways available upon morphine formation, in humansand other animal species studied, undergoes biotransformation by hydroly-sis (68). The first, rapid deacetylation yields 6-0-monoacetylmorphine(6-MAM) (30), whose observed pharmacological activity is equipotent tomorphine (69). The identity of the enzymes responsible for this hydrolysishas not been established. In plasma, on the basis of in vitro experiments,serum cholinesterase is believed to be responsible; however, human serumcannot hydrolyze 6-MAM to morphine (70). This second, slower deacetyla-tion releases morphine, the major urinary metabolite, which accounts for50-60% of an administered dose. Nearly all tissues can hydrolyze 6-MAMto morphine (71), but studies have shown that liver tissue exhibits thegreatest ability and brain tissue the least (72), furthering the belief that6-MAM is an important mediator of the pharmacological response toheroin. Heroin thus acts as a pro-drug, providing concentrations of activemetabolites 6-MAM and morphine to the systemic circulation, as deter-mined by route of administration (100). The secondary amine metabolites,namely, norheroin (41) and 6-acetylnormorphine (40), are 20 times lesspotent (mice) than their N-methyl derivatives, and both resemble mor-phine rather than heroin in their onset, peak, and duration of activity (73).

The narcotic antagonists naloxone (46) and naltrexone (48), althoughdisplaying species differences in metabolic disposition, produce 6 ,,_hydroxyl and/or 6j3-hydroxyl metabolites as a result of the reduction of the6-keto group (Scheme 1-8) (74). In humans and rabbits, for naloxone, theconjugation product naloxone-3-glucuronide (47) is the primary metabo-lite, although in the chicken the major metabolite is N-allyl-14-hydroxyl-7,8-dihydronormorphine-3-glucuronide (49), the 6,,-hydroxyl reductionproduct. Naltrexone in humans yields a metabolite with the 6j3-hydroxylconfiguration, N-cyclopropylmeth yl-14-hydroxyl-7 ,8-dih ydronorisomor-phine (52), while in the chicken the metabolite is again the 6,,-epimer(51). Little of the 6j3-hydroxyl naloxone metabolite (SO) is produced inhumans. The antagonist (naloxone, naltrexone) potency profiles, as well asagonist (hydromorphone, hydrocodone) profiles, have been shown to besensitive to functional group changes at the C-6 position. Both antagonistsdisplay a separation of potencies in the 6,,- and 6j3-0H metabolites whencompared to the ketone parents. The relative order for analgesic antago-nism is naloxone/naltrexone > 6,,- > 6j3-0H metabolites. In both an-tagonist series, the hydroxy metabolites are of lesser potency and sloweronset of action than the ketones, so that their actual contribution to theantagonist activity of the parent compounds is doubtful (74).

II

II The Biosynthesis and Metabolism of Morphine 19

46

47

(R=B)

(R=

~2H

OB

BOOH

48

B

ou

B

OB

Scheme ].8. Metabolites of naloxone and naltrexone.

C. Biotransformation in Papaver Species

Metabolites of the Papaver species h~ve been shown to be. bothalkaloidal and non alkaloidal (75). The major degradatlve pathway IS theinitial rapid demethylation to normorphine (34), a. step shown to beirreversible occurring solely in stem latex, and makmg both the actIvesynthesis a~d degradation rates for morphine very high (76)..This rap~dturnover has led to the belief that morphine plays an actIve role mmetabolism, acting perhaps as a specific methylating agent. Subsequentdegradation of normorphine yields large nonalkalOldal compounds (77)that account for 80% of morphine metabohtes (78).


53 54

55

Scheme 1-9.

56 (R=H)

57 (R=CH3)

Polar metabolites of Papaver species: the N-oxides.

Other polar metabolites (Scheme I-9) in P. somniferum have beencharacter~zed as the two ISOl~eric N-oxides of morphine (55, 56) and theone N-oxIde of code me m WhIChthe N+-O- bond is axial (57) (79). BothoXIdes of thebame (53, 54) have been isolated as natural metabolites in Pbracteatum. .

D. Morphine Disposition

1. Eli'!'ination from Plasma Previous confusion about the dispositionof morphme resulted mamly from the different analytical methodologiesand protocols used for measurement (80). Recently, however, theIssue has been clanfied by the use not only of radioimmunoassay (RIA)(81) but also of the newly developed, more precise, and more sensitivegas-lIqUId .chromatography (GLC) technique for detection (82). Thepharmacokmehc profile of morphine following intravenous administration

II The Biosynthesis and Metabolism of Morphine 2t

V2Peripheral

tissue

V3Peripheral

tissue(low blood flow)

Morphine;,

VI

Centralcompartment

Metabolized andexcreted drug

Fig. 1-1. Three-compartment model of morphine disposition in humans.

I

II

has been represented (83) by a three-compartment model (Fig. I-I) (83a)that coordinates the kinetics of the drug in various tissues and the kineticsof the pharmacological effects produced. The central compartment (V,) isthe recipient of the drug and the other two compartments (V2, V3) areperfused peripheral tissue; V3, however, comprises tissues with low bloodflow (84). Morphine is eliminated from the body primarily by hepaticbiotransformation via the central compartment.

The major mechanism, then, for removal of morphine from plasma isthe formation of water-soluble glucuronides in the liver; the majorelimination route is glomerular filtration and/or tubular secretion in thekidney. Clearance of morphine depends partly on the pH of tubular urine.Elimination via bile into the duodenum and feces is small (generally lessthan 3%), although studies vary widely in quantitizing this pathway. Freemorphine may be reabsorbed, however, by hydrolysis of the conjugates(about 20% of the dose in rats) via j3-glucuronidase activity of both theintestinal flora and mucosa (85). This hydrolysis is a prerequisite forenterohepatic recycling. Although urine and feces remain the main routesof excretion, saliva has also been reported.

Clearance of morphine from plasma depends on both the distributionand elimination processes. Distribution has been shown to be widespread.Saturable uptake, however, has been shown only by the kidney and brain,although the amount of drug accumulated in these tissues is smallcompared to that found in skeletal muscle. Subsequent elimination israpid, the rate-limiting step for this process being hepatic blood flow.Hepatic extraction and biotransformation are thought to be essentiallycomplete (83b); therefore, liver clearance is perfusion limited.

22 1 Morphine and Its Analogs II The Biosynthesis and Metabolism of Morphine 2J

Elimination consists of three distinct phases within a 6-hour period, afterwhich time 66% of the dose has been excreted in the urine (83). The first(1T)and second (a) phases represent the distribution to various tissues andorgans. Studies in which RIA and solvent extraction methods have beenused have demonstrated that typically, within 10 minutes, 97% of a dose iscleared from plasma and distributed. Concentrations of conjugated drugexceed those offree drug by this time. By 1-1.5 hr, metabolites account formore than 90% of the total morphine in plasma. The third ({3) terminalelimination phase consistently ranges from 1.5 to 2.5 hours, independentof dose, although the elimination half-life for the glucuronide is longer(86). Terminal elimination is actually biphasic: from 6 to 48 hours, theterminal elimination half-life has been shown to be 10 hours in rats(86,87).

Hepatic morphine clearance parallels hepatic blood flow, which isresponsible for regulating reuptake from peripheral tissues and delivery tothe liver. The rate of elimination, k8, is greater than the rate of uptakefrom peripheral tissues with low blood flow, kA, in the compartmentmodel. Although 80% (parenteral administration) of a dose is excretedwithin 8 hours and 90% after 24 hours, small amounts are still beingexcreted 72 hours later. This long half-life represents the fraction ofmorphine coming out of the tissues and being reabsorbed from entero-hepatic circulation (88). The long-term appearance of morphine in plasmamay be due to slow leaching from high-affinity binding sites like brain(86).

Morphine undergoes a high first-pass effect (88,89), which explains itspoor oral efficacy, since most of the drug never appears in the plasma but isextracted/metabolized in the intestinal walls and in the liver beforeconcentrating in the central plasma compartment (90). The significance ofmetabolism in the gastrointestinal tract seems to depend on lipophilicity,which affects the efficiency of gut UDP-glucuronyl-transferase activity, asevidenced by the observed small first-pass intestinal metabolism of thehydrophilic dihydromorphine (91).

Across various species, free morphine in urine accounts for 2-12% of anadministered dose in a 24-hour period and bound morphine for 20-42%when parenterally administered. Urinary excretion of morphine and itsconjugates accounts for 70-83% of a dose; 11-14% is accounted for bybiliary secretion (92).

humans, various routes have been employed, the major four beingintravenous (preferred), intramuscular, and subcutaneous injection andoral administration (94). Studies on the analgesia produced by eachroute and the accompanying kinetics have focused on the plasma levelsof drugs (94) and on renal clearance (95). However, no correlationbetween plasma levels and intensity of analgesia has been demonstrated.

Morphine distribution has been shown in animal species such as the rat,dog, and monkey in tissues such as kidney, lung, liver, spleen, and muscle.A major portion of morphine is in body muscle; only small amounts crossthe blood-brain barrier. Studies aimed at quantitating the tissue distribu-tion of drug have been limited mainly to rat brain. Although studies haveindicated a direct connection between plasma and brain, the equilibrationis slow due to the multicompartmentalization of morphine (96). There isno specific localization of morphine in the brain (97). Decline of analgesiaoccurs with a decrease in morphine concentrations in plasma and cerebro-spinal fluid (CSF), wherein uptake is slower. Elimination from kidney isprolonged compared to plasma pharmacokinetics.

RIA studies (94) in humans have shown that the most rapid absorptionof morphine occurs by the intravenous (iv) injection route (87b,98). Drugis delivered directly into the plasma, producing high free morphine plasmalevels within 15 min, but plateauing over the next 12 hr. The observedmaximum plasma level corresponds well to the reported time of maximumpharmacological effect, that is, minutes after injection. Low concentrationsof the drug persist in the plasma for up to 48 hours; this is thought to be dueto an albumin-binding phenomenon.

Second to the preferred iv route is the intramuscular (im) injection route(98). Absorbed both by passive diffusion and by active fluid transport,giving a systemic availability of 100%, the drug shows a maximum biologicaleffect in addition to a maximum serum concentration 60-90 minutes afteradministration. Equally efficacious is the subcutaneous (sc) injection route,since the absorption and distribution rates seem to be similar to those ofthe im route. The sc route gives a concentration equivalent to that of the ivroute at a 15-min interval. From 15 min to 3 hours, plasma levels are higherwith either the im or the sc route than with the iv route. However, at 6-9hours after administration, all parenteral routes show equal values, butwith an equilibrium plateau after 1-1.5 hours.

Oral administration is the least preferred route. It results in less than20% of the maximum plasma level of free morphine, which is produced 15min to 1 hour after an equivalent iv dose. In all studies, early oral freemorphine plasma levels were lower than those from parenteral routes, butequivalent concentrations for all routes were reached after about 9 hours.Neither plasma nor urine concentrations of free morphine were high; in

2. Dependence on the Route of Administration Morphine metabo-lism is largely dependent on the route of administration, and therefore alsoon the rates of absorption and distribution (93). While plasma levels aredetermined by the route of administration, plasma half-lives are not. In


contrast, the concentration of conjugated morphine, produced within themucosal cells of the small intesiine and the liver, was 16 times the freemorphine concentration in plasma after I hour. Factors contributing tothese observed effects of poor oral efficacy are thought to be not only thelow pH of gastric fluid and the high pK. of morphine, causing extensiveionization, lipid insolubility, and poor absorption, but also (in fact, mainly)the high hepatic extraction ratio determined by blood flow and causingextensive first-pass effects (90). Thus, only about 30% of an oral dosereaches the systemic circulation (98). Any absorption most likely occurs inthe duodenum, where the h(gh pH provides a favorable environment and alarge surface area exists.

In summary, the initial free morphine plasma levels are highest withthe iv route of administration, but the distribution, metabolism, andexcretion are also more rapid. After a longer time interval (15 min to 3 h),plasma levels are highest with the two other parenteral routes. Oral

. administration results in insignificant plasma morphine levels; however,the concentration of morphine conjugates is high.

Plasma levels of conjugated morphine are initially highest again withthe iv route. All routes result in similar values after about I hr. From 2-3to 9 hours, however, concentrations following oral administration arehighest. Cumulative 48-hr excretion of morphine conjugates is similar viaall routes, accounting for 60-80% of the administered dose, although ata I-hour interval the excretion of conjugates is highest with the iv route(95).

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........

I

References 25

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22,2129 (1973).68. S. Y. Yeh, R. L. McQuinn and C. W. Gorodetzky, J. Pharm. Sri. 66, 201 (1977).69, E. R. Garrett and T. Gurkan, J. Pharm. Sri. 69, 1116(1980).70. O. Lockridge, N. Mottershaw-Jackson, H. W. Eckerson, and B. N. La Du, J. Pharma.

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2.

Biological Effects of Opioids

by Donna Hammond'

I. Introduction .. . ..II. Multiplicity of Opiate Receptors

III. Analgesia. . .IV. Respiratory Depression.V. Gastrointestinal Motility

VI. Dependence Liability.VII. Summary .. ..

References . . . .

2931353738394041

I. Introduction

In the mid 1970s, research in the field of opioid pharmacology wasgalvanized by several significant discoveries. In 1973, Pert and Snyder (1)and Terenius (2), as well as Simon et al. (3), demonstrated that opiatesbound with high affinity to homogenates of brain in a saturable andstereospecific manner. Furthermore, the affinity of the opiates for thisbinding site closely paralleled their in vivo (4) and in vitro (5) potencies.Using biochemical techniques, these studies demonstrated the existence ofthe "opiate receptor" previously hypothesized on the basis of pharmacolo-gical evidence. The high degree of stereoselectivity of opioids for thisreceptor first observed with dextrorphan and levorphanol was laterconfirmed with (+)- and (- )-morphine (6) and (+)- and (- )-naloxone (7).

Although the existence of receptors for substances endogenous to thebody (e.g., the neurotransmitter acetylcholine) had long been recognized,the existence of receptors for substances that were not endogenous to thebody, such as morphine, was a novel concept. Identification of an opiatereceptor therefore fueled the search for an endogenous morphine-likesubstance in the brain. In 1975, Hughes (8) identified a substance inextracts of brain that inhibited contractions of guinea pig ileum and mousevas deferens in a naloxone-reversible manner. Using opiate receptor-binding techniques, Pasternak et al. (9) and Terenius and Wahlstrom (10)

,Department of Biological Research, G. D. Searle & Co., Research and Development

Division, Skokie, Illinois 60077.

29

30 2 Biological Effects of Opioids II Multiplicity of Opiate Receptors 31

Table 2-1

Biological Effects of Opiatesbe provided in one chapter. Consequently, this chapter focuses on theinteractions of opioids with the different opiate receptors and brieflyreviews those opioid effects of greatest clinical relevance: analgesia,inhibition of gastrointestinal transit, and respiratory depression and de-pendence (physical and psychic). For a more comprehensive review ofopioid pharmacology, the reader is referred to several excellent mono-graphs and texts (24-26).

Excitation (feline, equine)Sedation (human, primate, rodent)

Miosis (rodent, human)Mydriasis (feline, primate)

Euphoria (in the presence of discomfort)Dysphoria (in the absence of discomfort)Nausea and emesisAnalgesia

AntitussiveRespiratory depression

Inhibition of gastrointestinal transitUrinary retentionTolerancePhysical dependence

II. Multiplicity of Opiate Receptors

Two approaches have been utilized in studies of the opiate receptor. Inthe first, the pharmacological profile of a series of prototypic opioidagonists and antagonists was carefully characterized using behavioral,physiological, or pharmacological measures. This approach was used in theearly studies of Martin et al. (23) and Lord et al. (27). Using the chronicspinal dog. Martin et al. (23) evaluated the effects of a series of opioids on alarge number of physiological functions including pulse rate. respirationrate, temperature, pupil diameter, behavioral state. physical dependence,and nociceptive reflexes. The effects of the opioids could be classifiedaccording to three syndromes (see Table 2-2 of ref. 23) suggesting theexistence of three distinct opiate receptors. These receptors were termedJ.L, K, and (J". The J.Lreceptor, for which the prototypic agonist wasmorphine, was associated with bradycardia, miosis, respiratory decelera-tion, indifference, and analgesia. In contrast, the (J" receptor was associatedwith tachycardia, mydriasis, respiratory acceleration, and delirium; itsprototypic agonist was SKF 10,047 (N-allylnormetazocine). The K receptorwas associated with miosis, analgesia, sedation, and little change in pulseor respiratory rate; its prototypic agonist was ketocyclazocine.

The studies by Lord et al. (27) utilized a similar pharmacologicalapproach in investigating the effects of a series of opioids and opioidpeptides on electrically induced contractions of smooth muscle. Theauthors hypothesized that the relative potencies of a series of opioidsshould be closely correlated among a variety of in vitro assay systems if theopiate receptor population of these systems was identical. The heter-ogeneity of opiate receptors in different tissues was made immediatelyapparent by this study. Thus, the opioid pentapeptides [Met]- and [Leu]-enkephalin were more potent inhibitors of the electrically induced contrac-tions of mouse vas deferens than of guinea pig ileum. Conversely,morphine was more potent in the guinea pig ileum than in the mouse vasdeferens preparation. Furthermore, the concentration of naloxone re-quired to inhibit the actions of the pentapeptides in the mouse vas deferens

similarly demonstrated a substance in brain extracts that displaced thebinding of radiolabeled opiates. These substances were subsequentlyidentified as the pentapeptides, [Metjenkephalin and [Leu]enkephalin(II ,12). An additional morphine-like peptide of larger molecular weight,i3-endorphin, was isolated from pituitary extracts by Goldstein and col-leagues (13,14). Currently, three separate, individually gene-derived fami-lies of endogenous opioid peptides are recognized: the enkephalins, theendorphins, and the dynorphins (15-18) (d. Chapter 11). The recentisolation of morphine itself from bovine brain (19) and frog skin (20) isparticularly interesting in light of the past 10 years of research effort toidentify and isolate endogenous morphine-like substances. However, theorigin of this morphine remains to be identified.

As early as the 196Os, Portoghese (21) and Martin (22) suggested thatopioid analgesics interacted with multiple receptors or with multiple modesto a single receptor. However, these concepts were not vigorously pursuedagain until 1976 when Martin et al. (23) examined the pharmacologicalprofile of morphine and its cogeners in the chronic spinal dog and identifiedthree different syndromes. They attributed these syndromes to interactionsof the prototypic opioid agonists with three distinct receptors. Thus, on thebasis of pharmacological evidence, Martin hypothesized the existence ofnot one but multiple opiate receptors. This subsequently sparked anequally attractive hypothesis, still being examined today, that the differentbiological effects of opioids are mediated by different opiate receptors.

Because the biological actions of opioids are numerous, diverse andcomplex (Table 2-1), an exhaustive review of opioid pharmacology cannot

32 2 Biological Effects of Opioids

was ten times that required to inhibit the actions of morphine in the sametissue.! Together, these observations suggested the existence of two typesof opiate receptors present in differing amounts. The first, to whichmorphine bound with high affinity, was termed the I" receptor; it was thepredominant opiate receptor in guinea pig ileum. The second, to which thepentapeptides bound with high affinity, was termed the 0 receptor; it wasthe predominant receptor species in the mouse vas deferens. Using asimilar approach to compare the potencies of morphine and benzomor-phans in the guinea pig ileum and mouse vas deferens preparations,Hutchinson et al. (28) concluded that certain novel benzomorphans boundto a receptor distinct from that bound by morphine. This receptor was latersuggested to correspond to the K receptor postulated by Martin et al. (23).The rabbit vas deferens has been demonstrated to contain a preponderanceof K receptors (29).

The opiate receptor has also been characterized biochemically using anumber of different approaches (30). If the opioid was available inradiolabeled form, the kinetics of its saturable, stereospecific binding wereexamined using analyses of saturation curves to determine the equilib-rium dissociation constant (Kd) and the number of binding sites (Bmax).In an alternative approach suitable for use with ligands that were notradiolabeled, the affinity of the unlabeled ligand for a receptor wasestimated from its ability to displace the binding of radiolabeled ligands ofknown characteristics. Finally, very elaborate "selective protection" stu-dies were conducted in which a specific receptor among a mixed receptorpopulation was pre incubated with unlabeled ligand. This receptor wassubsequently "protected" from alkylation (irreversible inactivation) withdrugs such as N-ethylmaleimide and phenoxybenzamine. Such studieswere used to demonstrate the existence of different opiate receptors in amixed receptor population and to yield a functionally homogeneousreceptor population for study.

On the basis of the biochemical and pharmacological studies discussedabove, four subtypes of the opiate receptor have been proposed: 1", 0, K,and (]"(30-33). In addition, prototypic agonists for each receptor subtypehave been proposed. Table 2-2 lists the receptor subtypes and those

I Receptors with different binding properties can be differentiated in a mixed population ofreceptors through the use of antagonists. The efficacy of an antagonist against an agonist at a

particular receptor may be expressed in terms of its equilibrium dissociation constant Ke, that

concentration of antagonist that requires a doubling of the agonist concentration to achieve

the same pharmacological effects measured in the absence of the antagonist. The equilibrium

dissociation constant may also be expressed as its negative logarithm, or pA2. The pAz values

obtained with an antagonist against an agonist in different tissue preparations will differ if the

agonist interacts with different receptors in the preparations.

..,....

Table 2.2

Receptor

Prototypic Agonists for the Opiate Receptors

Agonist

Mu(,,)

Delta (5)

Kappa (K)

Sigma «T)

Morphine

Dihydromorphine

DAGODADLEDTLET

Tyr'D-Ala-Gly-MePhe-NH(CH2)20HTyr-D.Ala-Gly-Phe-D-LeuTyr-D- Thr-Gly-Phe-Leu- Thr(CH,hC-s s.-C(CH,h

I ITyr-NHCHCO-Gly-Phe-NHCHC02H

DPen2 ,LPen~ -enkephalin

Ethylketocyclazocine

Dynorphin'_9

HO

Tyr-Gly.Gly-Phe-Leu-Arg-Arg-IIe-Arg

~NJ;JNMe

V-50,488

Cl

Cl

SKF 10,047 (N-allylnormetazocine)

HO


opioids commonly considered to be prototypic ligands. Although someopioids exhibit as much as 100 times greater affinity for one receptor thanfor another, it is important to realize that no opioid is truly specific for anyone opiate receptor subtype.2 Rather, opioids are discussed in terms oftheir selectivity and relative affinity for one receptor as opposed toanother.

Morphine is the prototypic ligand for the ILreceptor. Other compoundsthat have greater affinity for the IL receptor include dihydromorphine,phenazocine, etorphine, and levorphanol (30,33). Certain en kephalinanalogs also bind preferentially to the ILreceptor. Although the I) receptorwas initially viewed as the "peptide" receptor, it quickly became apparentthat modification of the C-terminus of the pentapeptides decreased theiraffinity for the I) receptor relative to the IL receptor (34-36). FK 33-824[Tyr-DAla-Gly-MePhe-Met-(O)-ol] (37,38) and OAGO [Tyr-DAla-Gly-MePhe-Gly-ol] (39) are two opioid pep tides that bind to the ILsite with 20and 100 times, respectively, greater affinity than to the I) receptor.Morphiceptin [Tyr-Pro-Phe-Pro-NH2] and certain of its analogs also bindto the IL receptor with much greater affinity than to the I) receptor (40).

The current prototypic agonist for the I) receptor is oAla2-DLeu'-en kephalin (OAOLE). However, it is only three times more selective forthe I)site than for the ILreceptor (41). Thus, it is likely to be supplanted asa prototypic ligand by several of the more recently synthesized andsubstantially more I)-selective enkephalin analogs. These include OSLET[Tyr-DSer-Gly-Phe-Leu-Thr] (36,42) and OTLET [Tyr-DThr-Gly-Phe-Leu-Thr] (41), which are 8 and 23 times more selective for the I) receptor,respectively. Oimeric pentapeptide [Tyr-oAla-Gly-Phe-LeuNH],. (CH2)n(OPEn) (43) and tetrapeptide [Tyr-oAla-Gly-PheNH]2' (CH2)n (OTEn)(44) enkephalins in which the monomers are linked by methylene chains ofvarying length have also been determined to bind to the I) receptor withgreater affinity than to the IL receptor. In the OPEn series, OPE, has thegreatest affinity for the I)receptor, while OTE12 has the greatest affinity forthe I) receptor in the OTEn series. Conformationally constrained cyclic

2 Opioid compounds are frequently compared in terms of potency, affinity for a receptor,and selectivity between receptors. Estimates of potency and affinity are based on IC50 values(i.e., that concentration of drug that produces a 50% reduction of effect or displacement of a

radiolabeled ligand). The ratio of ICso values determined for the different receptors providesa measure of the relative potency of the compound at the different receptors but does notaddress the selectivity of the compound for a particular receptor. This approach is. however,quite useful in in vitro tissue bath preparations. Selectivity can be addressed in the

radiolabeled ligand displacement studies by conversion of the ICso values to Ki values. Theratio of Ki values provides an estimate of relative selectivity for a receptor. It should be notedthat estimates of potency, affinity, and selectivity differ among experimental preparations andbetween studies.

III Analgesia 35

analogs of enkephalin have also been prepared using penicillamine (13,13-dimethylcysteine) residues (45). Two of these rigid cyclic analogs, [DPen',DCys5]-enkephalinamide and [DPen',LCyss]-enkephalinamide, are 20times more potent at the I) than at the IL receptor. The correspondingcarboxylic acid terminal compounds, [DPen2,DCys5]_ and [Open2,LCys5]_enkephalin, similarly exhibit high affinity for the I)receptor (46). However,the most pronounced I)selectivity of this series has been observed with thebis-penicillamine analogs [DPen',LPen'J- and [open2,Dpen']-enkephalin(47). These analogs are 371 and 175 times more potent, respectively, at theI) receptor than at the IL receptor.

Ethylketocyclazocine, ketocyclazocine, and bremazocine bind to theK receptor with high affinity. However, these ligands are not very selec-tive for the K receptor, since they also bind relatively well to the ILreceptor (48). Recently, U-50488 (trans-3,4-dichloro-N-methyl-N-(2-(I-pyrrolidinyl)cyclohexyl]benzeneacetamide) and U-69593 (5a,7a,8f3-( -)_N-[7-(I-pyrrolidinyl)-I-oxaspiro[ 4,5]dec-8-yl]benzeneacetamide) have beendemonstrated to bind more selectively to the K receptor (49,50). Amongthe endogenous opioid peptides, the dynorphins exhibit high affinity forthe K receptor (51). The most selective of these is dynorphin'_9' which is10 times more selective for the K receptor than for the IL receptor (52).

SKF 10,047 is the prototypic opioid ligand for the a receptor. The readeris referred to the reviews by Zukin and Zukin (31,32) for an in-depth'review of this receptor and its relationship to phencyclidine.

In summary, four subtypes of the opiate receptor have been identified onthe basis of their different pharmacological profiles. In addition, bioche-mical and auto radiographic studies have demonstrated that these receptorsare distributed differentially throughout the central nervous system (CNS)and the periphery (54). These observations have led to the suggestion thatthe different opiate receptors may mediate the different pharmacologicaleffects of the opioids. Thus, since 1976, investigators have attempted, notalways successfully, to assign pharmacological significance to each of theopiate receptor subtypes. The following sections briefly review theseattempts.

III. Analgesia

A wide variety of behavioral tests are available to evaluate the potentialefficacy of an opioid as an analgesic. These tests differ in the type,intensity, and duration of the noxious stimulus; in the endpoint responsethat is measured; and in their sensitivity to inhibition by opioids. Thesetests include the writhing (55-57), formalin (58), tail flick (59), hot plate


(6(}), and flinch-jump tests (61) routinely performed in the rodent, the skintwitch response performed using the dog (62), and the discrete trial shocktitration procedure used in the primate (63,64). Table 1 of the review byMartin (24) includes a comparison of the efficacy of different opioids inthese various tests.

In addition to the analgesia produced upon systemic administration ofopioids, an animal's response to noxious stimuli can be attenuated orinhibited by injection of microgram amounts of opioids into the cerebralventricles, into certain nuclei of the brain stem, and into the spinal cordsubarachnoid space (65). These findings suggest that systemically adminis-tered opioids produce analgesia by acting at sites within the CNS. Thisconclusion is supported by studies demonstrating that the analgesiaproduced by systemically administered opioids can be antagonized bymicroinjection of opiate antagonists in the cerebral ventricles, spinal cordsubarachnoid space, or brain stem nuclei (66-70). Finally, it has beenproposed that the analgesia produced by systemically administered opioidsis the product of a complex interaction of the many sites in the CNS atwhich the opioids act (71-73). Thus, microinjection of a subeffective doseof opioids at both a supraspinal and a spinal site produces a profoundanalgesia that exceeds that anticipated on the basis of an additive effect atboth sites.

The analgesic activity of opioids was initially attributed to activation ofthe J.' receptor. This hypothesis was based in part on the differentialdistribution of the opiate receptor subtypes in the brain and the finding thatregions involved in the processing of nociceptive information were en-riched in J.' sites (74-76). Although the analgesic activity of K agonists suchas ethylketocyclazocine has been recognized since 1976 (23,77), this effectcould not be dissociated from their additional affinity for the J.' receptor. Aselective K agonist, U-50488, has been shown to produce analgesia (49).This observation, and the analgesic activity of K agonists that have a J.'antagonist rather than agonist activity (e.g., nalorphine), suggest thatactivation of K receptors also produces analgesia. In addition, K receptorshave been visualized in the spinal cord, a CNS site involved in theprocessing of nociceptive information (78). The analgesic activity of Sagonists, particularly after intracerebroventricular or intrathecal adminis-tration, has been demonstrated in several studies (79-82), as has theexistence of S receptors in regions of the CNS involved in the processing ofnociceptive information (74-76). Thus, it appears that the analgesicactivity of opioids cannot be attributed to activation of one particularsubtype of the opiate receptor.

Indeed, it is increasingly apparent that experimental conditions (species,test, agent, etc.) can significantly affect the conclusion~ drawn by studies

IV Respiratory Depression 37

that attempt to assign functional significance to a particular opiate recep-tor. The choice of species can be be an important factor. For example, only10% of the opiate receptor binding sites in rat brain can be characterized asK-like, in contrast to estimates as high as 40% in guinea pig brain (48,83,but see 50). Also, although K-like sites have been demonstrated in mouseand guinea pig spinal cord, they appear to be absent in rat spinal cord (50).The choice of analgesiometric test can also influence the results of suchstudies. Several investigators have demonstrated that analgesiometric testsutilizing thermal stimuli, such as the tail flick and hot plate tests, aresensitive indicators of the anal esic actions of J.' agonists but are insensitiveto the actIOns of K agonists 49,84 86). In contrast, analgesiometric testsutilizIng chemIcal stimuli, such as the ~hing test, are sensitive to theanalgesic actIons of both J.' and K agonists. Finally, the relative selectivity(or lack thereof) of the oplOld used as a prototypic ligand is also animportant factor. Therefore, the results of studies that attempt to attributethe in vivo effects of an opioid to an interaction with a specific receptor onthe basis of its in vitro profile must be reviewed with great care.

IV, Respiratory Depression

I

Respiration may be monitored using a number of different techniquesincluding measurement of respiratory rate, tidal volume, minute volume(the product of respiratory rate and tidal volume), the arterial tension ofC02 and O2 (also known as pC02 and p02), integrated phrenic nerveactivity, and responsivity to C02' Using these techniques, investigatorshave shown that opioids alter respiratory rate, rhythmicity, pattern, andminute volume (24,87). Morphine has been demonstrated to affect thefrequency and tidal volume control mechanisms of the respiratory centerindependently (88) and to depress the peripheral hypoxic drive to respira-tion (89). Opioids also decrease responsivity to C02 (24). For example,morphine, pentazocine, and nalbuphine shift the C02 stimulus-respiratoryresponse curve in humans to the right (24,89,90). Indeed, almost the entiredecrease in total respiration may be attributed to a failure of the respira-tory center to respond fully to C02 (88). Opioid peptides such as[Met]enkephalin, fJ-endorphin, and DAla2-DLeu5-enkephalin also depressrespiration (91-94).

Several studies have tried to determine whether the respiratory depres-sant and analgesic effects of opioids are mediated by the same opiatereceptor. The results of these studies indicate that the respiratory depres-sant and analgesic effects of opioids are mediated by different opiate

II

I


receptors. Thus, McGilliard and Takemori (95) and Pazos and Florez (96)reported that the apparent pAz value for antagonism of the analgesic effectof an opioid differed from the apparent pAz value for antagonism of itsrespiratory depressant effect. If these effects had been mediated by thesame opiate receptor, the pAz values would have been similar. In addition,pretreatment with selective, irreversible

I" antagonists such as {3-funaltrexamine (97) or naloxonazine (98) has been shown to antagonizethe analgesic effect, but not the respiratory depressant effect, of opioids.Taken together, the results of these studies indicate that the respiratorydepressant and analgesic effects of opioids are mediated by different opiatereceptors. It should be noted that the respiratory depressant effects ofopioids cannot be attributed to activation of one particular opiate receptorsubtype and that I" as well as Ii opiate receptors are involved in thedepression of respiration (24,92,94,96).

V. Gastrointestinal Motility

The decrease in gastrointestinal motility produced by opioids is a resultof an increase in the tone of portions of the stomach, small intestine, andlarge intestine and a decrease in the number of propulsive contractions ofthe small and large intestines (99,100). Both peripheral and central sites ofaction mediate the reduction in gastrointestinal motility produced byopioids (101-103). Thus, gastrointestinal transit of a charcoal orradiolabeled chromium "meal" is inhibited following intracerebroventricu-lar (101-103) or intrathecal (104) administration of opioids. Furthermore,the decrease in gastrointestinal transit produced by systemically adminis-tered opioids is attenuated by intracerebroventricular administration ofopioid antagonists (101,105,106). The results of these studies suggest thata portion of the gastrointestinal effects of opioids is mediated by siteswithin the CNS. A peripheral site of action is indicated by the finding thatopioids that do not cross the blood-brain barrier, such as loperamide, alsodecrease gastrointestinal motility (102). Ward and Takemori (106) havesuggested that the centrally mediated effect of opioids on gastrointestinalmotility is mediated by I" receptors, whereas both I" and Kopiate receptorsmediate the peripherally mediated effects of opioids on gastrointestinalmotility. Porreca and Burks (104) have similarly concluded that thecentrally mediated actions of opioids on gastrointestinal transit are medi-ated by 1", but not K, opiate receptors. These authors have also concludedthat the gastrointestinal effects of opioids exerted at the level of the spinalcord involve Ii as well as 1", but not K, opiate receptors (104).

I

VI Dependence Liability )9

VI. Dependence Liability

Drug dependence has been defined by the World Health OrganizationExpert Committee on Drug Dependence as

a state, psychic and sometimes also physical, resulting from the interaction between aliving organism and a drug, characterized by behavioral and other responses thatalways include a compulsion to take the drug on a continuous or periodic basis in order

to experience its psychic effects, and sometimes to avoid the discomfort of its absence(107)

This definition recognizes that there are two components to drug depen-dence, psychic and physical, and that psychic dependence can occur in theabsence of physical dependence. The definitions of psychic and physicaldependence developed by Eddy et al. (108) further clarify the differencebetween these two components of drug dependence. Thus, psychic de-pendence is defined as "a feeling of satisfaction and a psychic drive thatrequire periodic or continuous administration of the drug to producepleasure or to avoid discomfort." Physical dependence is defined as "anadaptive state that manifests itself by intense physical disturbances whenthe administration of the drug is suspended. . . . These disturbances, i.e.the withdrawal or abstinence syndromes, are made up of specific arrays ofsymptoms and signs of psychic and physical nature that are characteristicfor each drug type." The different abstinence syndromes and signs thatcharacterize withdrawal from prototypic drugs such as alcohol, ampheta-mine, morphine, and cannabis reflect the different peripheral and neuronalsubstrates on which these compounds act to produce their effects.

Several animal models of physical drug dependence have been de-veloped including the single-dose suppression test, the precipitated with-drawal test, and the primary dependence test. The single-dose suppressiontest is used to determine the ability of an opioid agonist to suppress theabstinence syndrome exhibited by opioid-dependent animals in the processof withdrawal. In contrast, the precipitated withdrawal test is used withopioid antagOllist analgesics or mixed agonist-antagonist analgesics todetermine their ability to precipitate an abstinence syndrome in opioid-dependent animals. The primary dependence capacity of the opioid isusually evaluated last. In this test, the opioid is administered frequentlyover a period of 30-45 days and is then abruptly withdrawn, at which timethe animals are monitored for signs of abstinence (109,110).

Animal models of psychic dependence have also been developed. Thereinforcing properties of an opioid can be evaluated by studies of its abilityto support or initiate self-administration. The rhesus monkey IS anexcellent species for these studies because it will self-admimster the


majority of the drugs self-administered by humans for nonmedical pur-poses (109). The discriminative stimulus properties of an opioid can beevaluated using a drug discrimination paradigm in which an animal istrained to press one lever (drug lever) after administration of a prototypicopioid and another lever (saline lever) after administration of a vehicle. Ifa test compound is substituted for the prototypic opioid and the stimulusproperties of the test compound generalize to those of the prototypicopioid, the animal will indicate this fact by responding on the drug lever.Importantly, the classificatio.n of opioids according to their discriminativestimulus properties, as indicated by the results of drug discriminationstudies in rodents and primates is strikingly similar to their classificationaccording to their subjective effect as reported by humans (109). The useof animal models to evaluate the dependence liability of opioids isdiscussed in greater detail in the monograph authored by the Committeeon Problems in Drug Dependence in conjunction with the NationalInstitute of Drug Abuse (110) and in the review by Woolverton andSchuster (109).

A detailed discourse on the psychic and physical dependence liabilitiesof various opioids is not within the scope of this section. This informationcan be obtained from several reviews (24,109) and from the annual reportsof the Committee on Problems in Drug Dependence. A review of in vivostudies of the dependence liability of opioids indicates that p.- andK-selective opioids have different dependence profiles. Thus, compoundswith preferential affinity for the K receptor did not completely generalize tothe discriminative stimulus properties of p. agonists (109,111-113; see alsoTable 7 of ref. 24) and were not self-administered by rhesus monkey(114,115), unlike p. agonists such as morphine. Furthermore, K agonistsdid not suppress the abstinence syndrome in morphine-dependent animals(77,114). Finally, the abstinence syndrome exhibited by animals' madedependent on K agonists was different from that exhibited by animals madedependent on p. agonists (24,49,77,114). The dependence profile ofselective 5 agonists has not been thoroughly examined at this time.

VII. Summary

Research on opioid pharmacology was galvanized in the 1970s by thedemonstration of the existence of an opiate receptor and the subsequentisolation and characterization of its endogenous ligands. At this point, atleast four subtypes of the opiate receptor have been well characterized (p.,K, and IT) and several others have been postulated (A, 0). Many studies

.....

I

I

References 41

have attempted to equate each receptor subtype with a particular biologic-al effect of the opioids, such as analgesia, respiratory depression, gastroin-testinal motility, and dependence. A brief review of the data to dateindicates that it has not been possible to assign a physiological significanceto one particular opiate receptor subtype. Rather, the different subtypesappear to mediate, to differing extents, many of the pharmacologicaleffects of opioids.

References

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t

3.Synthesis and Structure-Activity Relationships ofMorphine, Codeine, and Related Alkaloids

I. Syntheses of Morphine, Codeine, and Related Alkaloids . . . .II. The Structure-Activity Relationships of Morphine and Related

Compounds. . . . . . . .. ......A. Alteration of Existing Functional Groups and Structures on

Morphine . . . . . . . . . . . . . . . . .B. Insertion of Substituents in Nonfunctionalized areas .

III. Diels-Alder AdductsofThebaine . . . .. ....A. Ketone, Sulfone, Nitroso. Ester. and Nitrile AdductsB. Functionalization at C-19: Alcohols . .C. Opiate Receptor Probes. . . . . . . . .

IV. The Chemical Anatomy of Morphine and Its DerivativesA. The Chemical Anatomy of Morphine . . . .B. The Chemical Anatomy of Diels-Alder AdductsReferences

45

55

5679

101103126153155155155157

I. Synthesis of Morphine, Codeine. and RelatedAlkaloids

Morphine and codeine have been the subject of numerous successful andunsuccessful synthetic studies since the correct formulation of the grossstructure of morphine and codeine by Gulland and Robinson (1). Therelatively complex, unsymmetrical structures of morphine and codeinewere first constructed by the heroic synthetic efforts of Gates and Tschudi(2). A second, contemporary synthesis, which is not described here, alsoinvolved the construction of a suitable hydrophenanthrene and subsequentelaboration of the bridging amine ring (3). For a delightful discussion ofthese two syntheses by the author of the latter, see ref. (4). Subsequentsuccessful syntheses usually produced dihydrothebainone, which had pre-viously been converted to codeine and then to morphine by Gates andTschudi, or other intermediates previously converted to these alkaloids.Until recently, the syntheses of these complex alkaloids have beenprimarily academic exercises aimed at developing new synthetic methodol-ogy, not commercial attractiveness. The shortfall in supply in the early1970s stimulated new efforts to design a commercially viable synthesis ofmorphine and codeine.

The first synthesis of morphine by Gates is illustrated in Scheme 3-1 (2).It started with the readily available dye intermediate, 2,6-dihydroxy-

45

OH OHa,b } c,d,e

>63%

p,qHO r.s.t

48% 24%HO C6H5C02

1HO 0

OHOCH3

+ 7-hydroxy isomer

JQJ~OHOCR3

f q,b,C,d,e>)80%

C6H5C02

c,r,s,u,t m) )6% 65%OCH3

OCH3 0h,i) g 583% 97%

)

0

0 0

0

j

66%)

CH30 CH30

CH30

2 3

CH30

1,m,nCH30

79%)

4

46 3 Synthesisof Morphine, Codeine, and Related Alkaloids I Synthesis of Morphine, Codeine, and Related Alkaloids 47

NO

v )34%

k

50%)

Codeine Morphine

Scheme 3.1. (cont.) Reagents: p, potassium hydroxide, diethylene glycol, 225°C; q,potassium tert-butoxide, benzophenone; T, bromine; s, 2,4-dinitrophenylhydrazine; t, ace-tone, HCI; u, pyridine, beat; v, pyridine hydrochloride, 220°C.

o

naphthalene (1) and involved the preparation of dienophilic ortho-quinone(2), which eventually comprised the A- and B-rings of morphine. Thedienophile (2) was obtained in about 20% overall yield starting from 1. ADiels-Alder reaction of 2 with butadiene generated the hydrophenan-threne (3). The Diels-Alder adduct (3) contained a cyan om ethylene groupin the proper array for eventual transformation into the nitrogen-containing ring of morphine. Furthermore, as a result of the Diels-Alderreaction, a strategically placed double bond was introduced. This doublebond served as the key for the introduction of the allylic hydroxyl group inring C. Reduction of 3 led to saturation of the enolic double bond,

>28%

Scheme 3-1. The first synthesis of morphine by Gates.1952. Reagents: a, benzoylchloride, pyridine; b, nitrous acid; c, PdlC, H2; d, ferric chloride; e, sulfur dioxide; f,dimethyl sulfate, potassium carbonate; g, hydroxide; h, ethyl cyanoacetate, triethylamine; i,potassium ferri cyanide; j, butadiene; k,

H2' copper chromite; I, Wolff-Kishner; m,lithiumaluminum hydride; n, Eschweiler-Clarke; 0, dilute sulfuric acid.

r

48 3 Synthesis of Morphine, Codeine, and Related Alkaloids

fonnation of an imino-lactone, and an unprecedented free radicalrearrangement to form the lactam (4). This lactam contained four of thefive rings found in codeine and morphine. Unfortunately, at this point, as aresult of the reduction, the incorrect stereochemistry was generated atC-14 (morphine numbering). Subsequent steps adjusted the oxidation levelof the molecule that ultimately led to the enone (5). Introduction of theenone labilized the proton at C-14, leading to the thermodynamicallypreferred cis-ring fusion. Closure of the furan ring and reduction of theketone furnished codeine, which was demethylated in molten pyridinehydrochloride to yield morphine, some 150 years after its isolation fromthe opium poppy. The overall yield for the synthesis shown in Scheme 3-1was 3.5 x 10-3%.

Subsequent efforts at the total synthesis of the opium alkaloid haveutilized either a biomimetic route in which a phenolic 1-benzyltetrahydroisoquinoline is oxidized to a morphinandienone that isconvertible to thebaine and thence to morphine, or an electrophilicreaction of a suitably functionalized, partially hydrogenated isoquinolineto form the morphinan carbon-nitrogen skeleton. Although not all knownsyntheses of morphinan will be discussed, selected examples of the aboveapproaches are illustrated.

With the biomimetric approach, the control of product distributionratios and the sensitivity of the morphinan-dienone to subsequent trans-formations have been frequent and major problems. An example of thisapproach is illustrated in Scheme 3-2 (5). In this synthesis, a benzyltetrahy-dro-isoquinoline, N-carbethoxynorreticuline (6), is oxidized with thal-lium(lII) to give the salutaridine analog (7), a morphinandienone. Hydridereduction then gives the epimeric salutaridinols (8), which are subsequent-ly dehydrated in unspecified yield to form racemic thebaine. It has sincebeen demonstrated that a variety of oxidizing agents and nitrogen-protecting groups are compatible with morphinandienone fonnation inreasonable yields (6). However, as illustrated in Scheme 3-3, attempts atsalutaridine (10) formation using a Pschorr reaction on the aminobenzyl-isoquinoline (9) gave vanishingly small yields (7). The entire concept of abiomimetic approach had previously been investigated using opticallyactive material derived from opium (8).

In the alternative approach to morphine alkaloid synthesis, the majormethod for construction of an azacarbocyclic ring system in morphinedepends on the Grewe cyclization (9). The transformation of 12 into 13 inScheme 3-4 is an example of this type of electrophilic subsfitution. In thisapproach, dihydrothebainone (15) has been the usual objective. However,predominant cyclization to morphinans with the wrong oxygenation pat-tern, lengthy synthetic routes requiring symmetrical I-benzyl substituents,

.,.Synthesis of Morphine, Codeine. and Related Alkaloids

a

23%

6

OH

49

>

o

7

8 Thebaine

Scheme 3.2. A biomimetic synthesis of thebaine proceeding from a I-benzyltetrahydro-

isoquinoline. Reagents: (a) 1.0equiv. thallium trifluoroacetate; (b) lithium aluminum hydride;

(c) hydrochloric acid.

9Scheme 3-3.

10 Salutaridine

Reagents: (a) sodium nitrite, N-sulfuric acid; (b) 70"C.

and the failure of the reaction with compounds substituted to generate thecorrect oxygenation pattern have hindered synthetic efforts in this area.Methods have now been developed to circumvent many of these problems(10).


a,b

87%),

-

HO

OH

11 12

C6H5I

N-N

O~ II

N_NOH

d >45%e

~75%

13 14

15 (-) -Cihydrothebainone

Scheme 3-4. Grewe-type syntheses of morphine alkaloids using symmetrically substituted1.benzylisoquinolines. Reagents; a, hydrogen, Pt/C, fonnaldehyde; b, lithium/ammonia;c, hydrochloric acid; d, 5-chloro-l-phenyltetrazole, potassium carbonate; e, hydrogen, Pd/C.

When a symmetrically substituted I-benzylisoquinoline is used to enterthe morphine alkaloid series, it is necessary ultimately to remove the extrasubstituent. An example of such a process is illustrated in Scheme 3.4 (11).The symmetrical, protected phenolic hydroxyl groups in the 3' ,5' -positionsof the I-benzyl substituent in the optically active 11 ensure the location ofthe hydroxyl group in the correct position in 13. After 11 is subjected to theBirch reduction, the resultant (12) cyclizes to the morphinan derivative(13), which has the required phenolic hydroxyl at C-4 and an extra one at

T I Synthesis of Morphine, Codeine, and Related Alkaloids 51

C-2. The extra phenolic group is removed by selective use of theMusliner-Gates reaction (12) to generate optically active dihydrothe-bainone (15), which is then converted to codeine and morphine. A majorproblem with this approach is the difficult synthesis of the appropriatelysubstituted phenylacetic acid precursor to compound (11).

The most straightforward approach to the synthesis of opium alkaloidsachieved so far is shown in Scheme 3-5. This synthesis illustrates thesuccessful execution of a modified Grewe-type synthesis of optically activedihydrothebainone (15), codeine, and morphine in an overall yield of15-20% from meta-methoxyphenylethylamine (16) (13). Racemic tetrahy-droisoquinoline (17) was readily resolved with tartaric acid into its opticalantipodes. The undesired enantiomer could be recycled readily (14). AfterBirch reduction, the amino group was protected as its formamide deriva-tive (18). Bromination ensured that 19 would cyclize correctly to form 20,which would be converted readily to (- )-dihydrothebainone (15), (-)-dihydrocodeinone (21), and (- )-nordihydrocodeinone (22). The versatility

CH30

.:, ) lQj)Hd'

CH3O""~NH2

J9l CO Ho '+ 0 2

CH30OH

16

b,c'--7

86'

o

~'6'OH

~'4%

OH

---4OH 60%

18 19 20

Scheme 3-5. A potentially commercial total synthesis of morphine and codeine. Reagents:a, 200°C, neat, argon; b, phosphorus oxychloride, acetonitrile; c, pH 4-5, NaCNBH3;d, Lijammonia; e, phenyl formate; C, methane sulfonic acid, ethylene glycol; g, N.

bromoacetamide; h, aqueous formic acid; i, triftuoromethane sulfonic acid.

6 ~4B%N

I 23 ICH3 CH3

@:OCH3

= OCH3

f )60%

H25

@:OCH3

~OCH3h > H2C

95%

-CHO

CH30

j,k,l ))CH3O )

B1%

52

j

92%)

22Nordihydrocodeinone

q

90%

3 Synthesis of Morphine. Codeine, and Related Alkaloids Synthesis of Morphine, Codeine, and Related Alkaloids

~100%

c,d,e~

80% 15 Dihydrothebainone

iBO% >

n,g,o,h,p

>67% 9

95%

21Dihydrocodeinone Codeine

) Morphine

Scheme 3.5. (cont.) Reagents: j, hydrochloric acid; k, bromine/acetic acid; I, sodiumhydroxide; m, hydrogen, Pd/C in the presence of acqueous formaldehyde; n, trimethylortho-

formate, acid; 0. potassiumtert-butoxide, DMSO; p, lithium aluminum hydride; q,boron

tribromide.

of this approach allows the preparation of both enantiomers in the norseries of codeine and morphine, as well as a wide variety of agonists andantagonists, by functionalization of the secondary amine in 22. Improvedprocedures allow the ready preparation of codeine from either IS or 21(15), and a rapid, high-yielding de methylation then gives morphine(16,17). The overall yields of natural (or unnatural) morphine, codeine,and thebaine are about 25% from meta-methoxyphenylethylamine withonly 6-8 isolated intermediates and the reactions have been run on a largescale (16).

An alternative general approach to morphine-based analgesics thatproceeds from 4-arylpiperidines has been described (18,19). The aryl-piperidines themselves function as analgesics. They are subsequentlyconverted into octahydroisoquinolines possessing a phenyl-substitutedbridgehead position (20). The synthesis is illustrated in Scheme 3-6. The

2B

53

24

~::)

H26

Morphine

Scheme 3-6. The 4a-phenyloctahydroisoquinoline route to the opiu~ alkaloids. Re~g~nts:a, 2,3-dimethoxyphenyllithium; b, p-toluene sul~onic acid, tolue~e, 11.0 ~; c, n-butYII.lthIU~~d, H2C=C(CH2Br)CH2CH2Br;e, sodium iodide; .f, perchlonc. aCid m met~anol, .g,

1-azomethane; h, dimethyl sulfoxide; i, boron triftuonde: -urc.; J, mes~1 chlonde, tnethyamine; k, lithium triethylborohydride; I, osmium tetroxide, sodium penodate.

OH OR2

29 30 R1 R2 H

31 R1 CH3, R2 - H

32 R1 R2 . CH3CO

R1

40 R1

41 R1

42 R1

43 R1

44 R1

4S R1

48 R1


B, R2 OH

R2 = H

OCH3, R2 - OH

OCH2CH3, R2 = OB

OCH2C6BS' R2 OH

OC(CH3)3' R2 OH

02CCH3' R2 . OH

49 R H

46

II The Structure-Activity Relationships of Morphine and Related Compounds 55

arylpiperidine (23) is deprotonated to form the enamine anion, whichcondenses with an allylic dibromide to generate the octahydroisoquinoline(24). Enamine protonation under kinetic control yields the cis ring-fusediminium salt (25), which, after conversion to the aziridinium cation (26), isoxidized and then cyclized to the morphinan derivative (27). This syntheticsequence generates the incorrect trans-stereochemistry at the BC-ringjunction in 27. After conversion of the exo-methylene group into astrategically placed ketone in 28, classical transformations as shown inScheme 3-1 allow epimerization to the thermodynamically more stable cisring fusion and then conversion to morphine and codeine alkaloids. Thissequence is interesting because it appears that only compounds containingthe exocyclic methylene group like 26 undergo cyclization. Compoundscontaining oxygenated functions fail (21).

II, The Structure-Activity Relationships ofMorphine and Related Compounds

The use of opium for a variety of medical disorders and analgesia can betraced to the beginning of prehistory. However, attempts to treat pain withdiscrete chemicals began about 200 years ago with the isolation of mor-phine from opium. Although the addiction liability and the toxicity ofmorphine were recognized early on, it was the invention of the hypodermicsyringe by Wood in 1853 and the subsequent abuse of parenteral morphinethat illustrated the social problems of this drug. These and related eventsinitiated the search for a safe, nonaddicting opioid.

Even before the correct structure of morphine was known, chemicalinvestigations were begun to alter its pharmacological effects. One of theearliest derivatives was the diacetyl compound heroin, the heroic drug,which was initially introduced as an antidote to morphine addiction (22).Over time, clinical experience invalidated this claim. In subsequent years,a variety of other morphine derivatives were introduced, but none weredemonstrably superior to morphine.

In 1929, the first systematic studies of the structure-activity relationships(SAR) among derivatives of the opium alkaloids were begun under thedirection of the Committee on Drug Addiction of the National ResearchCouncil (23). This early work formed the data base for the eventualsemi-systematic investigation of the opioid SAR. The SAR of morphineand related derivatives have been reviewed extensively over the years(24-32).

A. Alteration of Existing Functional Groups andStructures on Morphine

In examining the structure of morphine, besides its optical mirror image, a b,csubstituents that can be modified without directly affecting the basic ) )

nucleus are the phenolic function at C-3, the alcohol at C-6, the doublebond at C-7, and the methyl group on the basic amine. The stereo- CH30 OB

chemistry of these substituents and the stereochemistry at the BC-ring IBoneopine34 35

junction have also been investigated. Although these groups and stereo-chemical relationships have not been varied systematically to determineSAR correlations, a suffiGient data base currently exists to create one.

1. Enantiomeric (+ )-Morphine and Its Analogs To define the enan- d a

tiomeric requirements of morphine's ability to produce analgesia and to) >

interact with its receptors, the (+ )-enantiomer of morphine was synthe- CH30sized (33). The absolute configuration of the morphinan skeleton of

36 37naturally occurring (- )-sinomenine (29) is enantiomeric to natural (-)-morphine. The synthetic pathway proceeding from (29) also allows thepreparation of (+ )-codeine (31) and (+ )-heroin (32), as well as (+)-morphine (30) (33,34). Since sinomenine (29) is a rare alkaloid and is

fattainable only with difficulty, a subsequent total synthesis has been edeveloped (13). The unnatural enantiomers of the alkaloids have shown no > )

"-analgesic activity in standard screening tests for centrally acting analgesics,

"-

and (+ )-morphine (30) has minimal opiate receptor affinity (35). CH30 CH300 OH

trans-codeine38 39

56 3 Synthesis of Morphine. Codeine. and Related AlkaloidsII The Structure-Activity Relationships of Morphine and Related Compounds \7

2. Trans-Morphine Morphine possesses the cis-decalin type of junc-tion between rings Band C, while the aromatic ring and ether linkage forcethe Coring into the boat conformation. In the simplified opiate analgesicssuch as the benzomorphans, conversion of the cis-ring fusion to thetrans-decal in type of ring system furnishes superior analgesics whencompared to their respective cis-fused isomers. As a result, the synthesis oftrans-morphine (33) was undertaken to prepare a more potent morphine-based analgesic. However, it can be readily seen that the introduction ofthe BC-trans ring fusion would severely distort the shape of the morphinering system. The morphine alkaloid isoneopine (34), which containsunsaturation at position 8, serves as the starting material for the prepara-tion of the desired trans-morphine (Scheme 3-7). The 6-,B-tosylate (35)slowly undergoes hydroboration, which after oxidative workup gives the8-a-alcohol (36) and, more importantly, generates the desired BC-transring fusion (36). Solvolysis of the tosylate (36) in the presence of lithiumcarbonate yields the 6-a-alcohol (37), which is the naturally occurringconfiguration. Because the 6-a-alcohol is hindered, it is possible to tosylatethe 8-a-alcohol selectively, giving 38, which, after elimination, introduces

HO OHtrans-morphine

33

Scheme 3.7. The first synthesis of trans-morphine. Reagents: at tosyl chloride. pyridine;b, diborane; c, hydrogen peroxide; d, lithium carbonate in reftuxing dimethylformamide; e,refluxing 2,4,6-collidine; f, lithium diphenylphosphide.

the requisite double bond at position 7, forming trans-codeine (39). Thestandard demethylation procedure employing pyridine hydrochlonde givesonly traces of the desired trans-morphine. The use of the diphenylphos-phide anion allows the isolation of trans-morphine (33), but in a yield ofonly 16%. The overall yield of trans-codeine (39) from isoneopine (34) ISarespectable 10% (37). A substantial improvement was made when It was


Table 3-]

Morphine trans-Morphine

Compound

Codeine 42Trans-Codeine 39MorphineTrans-Morphine 33

mpk, sc7.5

17.51.2

11.7

,.Hot plate activity.

discovered that bis-tosylate of diol (34), prepared from the tosylate ofisoneopine, undergoes solvolysis and elimination with potassium acetate inrefluxing dimethylformamide to yield trans-codeine directly in three stepsfrom isoneopine, with an overall yield of 30% (38).

In distinct contrast to simpler systems, conversion of the naturallyoccurring cis-ring fusion in morphine to the trans-ring fusion providedcompounds with disappointing analgesic activity (Table 3-1). For instance,trans-codeine was about half as potent as codeine in the hot plate assay.More significantly, the analgesic activity of trans-morphine was only 1/lOththat of morphine itself. The rather severe distortion of the C-ring intrans-morphine was thus not consistent with enhanced analgesic activity(38,39). However, in the morphinans (q.v.), the trans stereochemistrygenerally yields more potent analgesics than the cis.

3. The Phenolic Function at C-3 The phenolic group at C-3 inmorphine has been assumed to be important to its biological activity and itsability to bind to the opiate receptor. This concept has been tested by the~eductive elimination of the phenolic group and also the 6-hydroxyl group10 morphme (40). The 3-deoxy compound (40) is about one-third as potentan analgesic as morphine while possessing only 1/30th of its receptor-binding affinity. Surprisingly, the 3,6-dideoxy derivative (41) is equipotentas an analgesic and retains one-third of the receptor-binding affinity ofmorphine. The results indicate that the phenolic hydroxyl group generallyhas a greater effect on receptor binding than on analgesia and that the3-phenolic group is not essential for analgesic activity.


Table 3-2

EDso"

R A R A

CH, (47) 0.5H 0.6CH,CH, 0.3

CH)HCH,CH,

0.50.30.3

.. mpk, sc in mouse hot plate assay.

4. O-Alkyl and Acyl Substitution at C-3 An intact A-ring is, ingeneral, necessary for analgesic activity. Masking of the phenolic hydroxylby etherification or esterification generally causes a decrease in morphineanalgesic activity, with heroin being a notable exception. Methylationyields codeine (42), which is a weaker analgesic than morphine but iswidely used for the relief of mild to moderate pain and as an antitussive.Codeine is orally active, and its analgesic activity is attributed to itsmetabolic conversion to morphine (41). In terms of potency, codeine isabout 1/lOth as active as morphine when administered subcutaneously inthe mouse tail flick test. The ethyl ether (43) (Dionin) is somewhat morepotent than codeine, while the benzyl ether (44) is intermediate betweencodeine and morphine (25). The derivative (45), containing a bulkytertiary butyl ether, is inactive in the tail flick assay (42). Alkylation ofmorphine with N-(2-chloroethyl) morpholine generates pholcodeine (46),which is valuable as an antitussive and is superior to codeine as a centrallyacting sedative.

Although masking of the phenolic group results in a reduction of itsmorphine-like effects, the opposite is true of the alcoholic function at C-6;therefore, the diacetyl derivative (47) (heroin, diamorphine) has at leasttwice the potency of morphine. Heroin (47) and its lower acylhomologshave similar analgesic potencies in mice and high physical dependenceliabilities in monkeys (Table 3-2) (43). The activities of 6-monoacylatedderivatives demonstrate little difference from those of the diesters; allcompounds are two- to fourfold more potent than morphine. In contrast,3-acetylmorphine (48) and morphine are equivalent (44). These observa-tions indicate that rapid deacylation of heroin occurs at the phenolIc

a ba----7 ----7 ----;>

RO ROCH30 CH30

52 58

c d,e

1b-----0> ----7

RO RO

52 R CH3 55 R CH2OCH354 R CH2OCH3

60

RO

51 R

53 R

56 R

3 Synthesis of Morphine, Codeine, and Related AlkaloidsII The Structure-Activity Relationships of Morphine and Related Compounds 6t

57

~ ~Scheme 3.9. Synthesis of 713, 813-cycJopropylcodeine. Reagents: a, (CH3hSOCH2 -; b,

diazomethane, Pd(II); c, sodium borohydride.

the equivalent morphine j3-7,8-epoxide (53) failed due to A-ring degrada-tion (50). Successful synthesis of the desired epoxide started with protec-tion of the phenolic hydroxyl of morphine as its methoxymethyl ether andsubsequent oxidation of the 6-hydroxyl to the ketone (54). Base-catalyzedepoxidation with hydrogen peroxide then gave the epoxyenone (55).Reduction with sodium borohydride gave the 6a-hydroxy-7j3-8j3-epoxide (56), which, after removal of the protecting group, gave morphinej3-epoxide (53). Acetylation of 53 gave heroin epoxide (57) (51). All of theepoxides demonstrated dose-dependent analgesic activity. Not surpris-ingly, heroin epoxide (57) was the most potent, and all three epoxides (51,53, 57) were approximately twice as potent as their unsaturated parents.

The similarity of ole fins and cyclopropane derivatives with regard totheir chemical properties (52) and extrapolation to their biological effectsled to the replacement of the 7,8-double bond with a cyclopropane ring.The addition of dimethyloxosulfonium methylide to conjugated enones toyield cyclopropylketones is a general reaction of wide applicability (53).However, when this reagent was applied to codeinone (52) (Scheme 3-9),only methylene transfer to the ketone to form the exocyclic oxirane (58)

Scheme 3-8. Synthesis of codeine, morphine, and heroin epoxides. Reagents: a, methoxy-methyl chloride; b, silver carbonate; c, hydrogen peroxide, sodium hydroxide; d, sodiumborohydride; e, 1 N hydrochloric acid; C, acetic anhydride, pyridine.

position in the plasma and that the resultant 6-acetylmorphine is thespecies that penentrates the CNS (45).

5. The Importance of the 7,S-Double Bond The catalytic reduction ofboth morphine and codeine with hydrogen to yield dihydromorphine (49)and dihydrocodeine (50) is a straightforward reaction (46). The resultantdihydro compounds possess equivalent or slightly increased analgesicpotency compared to their unsaturated parents. For instance, dihydromor-phine (49) is equipotent to morphine in mice and has approximately2.5 times the potency in cats. From these observations, it is readilyapparent that unsaturation at C-7 is not essential for analgesic activity (47).

Codeine j3-7,8-epoxide (51) is a minor metabolite of codeine (4S) and isreadily prepared by base-catalyzed addition-elimination of hydrogen per-oxide to codeinone (52) (Scheme 3-8) (49). Several attempts to synthesize

7

HO 6{1

Double Bond C-6 Substituent Analgesic Potency Species

7.8 a-OH 1 (morphine) Mouse/J-OH 0.4 Mousea-OCH) 6 Mouse/J-OCH, 0.5 Cat=0 0.3 Mice

6.7 H 8 . RatCH) 15. RatCH:zCH) 4 Ratn-C4H<) 5 RatC6HS 2 Rat

Saturated H 8 Cata-OH 2.5 Cat/J-OH 0.7 Cata-OCH) 4 Cat/J-OCH, JO' Cat=0 4 Cat

~CH2 60' CatfJ-CH, 50' Cat

a Adapted, in part, from Table 2.2 of ref. 9.

62 3 Synthesis of Morphine, Codeine, and Related Alkaloids II The Structure-Activity Relationships of Morphine and Related Compounds 63

was observed (54). The oxirane (58) was equipotent to codeine in themouse hot plate test. Subsequent attempts to add various carbenes ordihalocarbenes to codeinone (52) were unsuccessful. The desired trans-formation was ultimately achieved by the palladium.catalyzed addition ofdiazomethane to 52 to form the 7/3,S/3-cyclopropylcodeinone (59), whichcould be reduced to 7/3,S/3-cyclopropylcodeine (60) with sodium borohy-dride (55). The cyclopropylcodeine (60) and codeinone (59) derivativeswere tested for analgesic activity in both the peripheral mouse writhingassay and the central rat tail flick assay and were compared with codeine.Peripherally, cyclopropylcodeine (60) is approximately five times moreactive than codeine, while centrally it is inactive in analgesic doses ofcodeine. On the other hand, cyclopropylcodeinone (59) is approximately20-fold more active than codeine both peripherally and centrally.

The reduction of the 7,S-double bond or replacement with epoxy orcyclopropyl isosteres thus appears, for the most part, to be consistent withthe retention of analgesic activity. Minimally, these substitutions retain theoriginal activity and can increase it slightly to several fold.

Table 3-3

The Effect of C-6 Substitution on Analgesic Potency a

6. The 6-Hydroxyl Group: Its Epimers, Isosteres, and Replacements Asignificant amount of work has been done on position 6 of morphine inaddition to epimerization of the alcohol, acylation, and etherification. Thisincludes oxidation to the ketone, replacement by halogen, and completeremoval of the oxygen. The majority of these studies are included in theoriginal work by Eddy and Mosettig (23). All of these compounds haveanalgesic activity, and they usually have greater analgesic potency anddependence liability than morphine. Additionally, many of these earlyanalogs also possess a reduced 7,S-double bond. The analogs are presentedin Table 3-3.

The synthesis of the majority of these compounds is usually straight-forward. Because of its Qigh potency, significant amounts of the 2:-meth lene dihydro compound (61) have been required, but because theinitial synt eSls was not capable of producing the amounts necessary fordetailed pharmacological investigations, a new synthesis was developed

I(.56j1 Protection of the phenolic hydroxyl as its methoxymethyl ether indmYdromorphinone (62) allowed the condensation with the Wittig re-agent, methylenetriphenylphosphorane, to generate the 6-methylene groupwith an overall yield of 'il'2P after deblocking. Detailed investigation hasindicated that 61 has a more rapid onset of action than morphine, andtolerance to the analgesic and sedative effects develop more slowly and to alesser degree than with morphine. Arterial pressure effects and intestinalmotility are also lessened, but both 61 and morphine have about the samerespiratory depressant activity.

Because the hydroxy group and the double bond in the Coring constitutean allylic alcohol, the rearrangements in this system have only relativelyrecently been untangled. The reactions of nucleophiles with codeinetosylate, as well as pseudocodeine tosylate, have been determined kineti-cally (57). Codeine tosylate (63), when treated with lithium chloride indimethylformamide at 40°C, undergoes an Sn2 reaction to give thea-chlorocodide (64), which rearranges by an Sn1' mechanism to form/3-chlorocodide (65) when heated at 120°C in the same solvent. Thestructures of these products have been rigorously defined using nuclearmagnetic resonance (NMR) techniques, thus eliminating much of theconfusion in the earlier literature (58). Pseudocodeine tosylate (66) reacts


opiate receptors in living animals. This occupancy is reversed by (-)_naloxone but not (+ )-naloxone (266).

The pharmacologically rare azido substituent has been introduced intothe 6-position of dihydromorphine (49) by an inversion process involvingconversion of the 6a-alcohol to the tosylate and displacement with azideto yield 6-deoxy-6j3-azidomorphine (67) (59). This compound is a remark-ably potent analgesic, being 150-300 times as potent as morphine in the ratand 50 times as potent as morphine in humans. It is also less toxic thanmorphine, with a low physical dependence liability in rats and monkeys,although withdrawal symptoms follow its use in humans (60). Clinicalstudies indicated that azidomorphine (67) functions as a typical opiate-likedrug in humans. It causes pupil constriction, subjective effects, andmorphine-like euphoria, yet suppresses the morphine abstinence syndrome(61). Other azido derivatives studied were 6-deoxy-6j3-azidocodeine (68),which is 13 times as powerful as morphine in the rat hot plate assay (62),and 6-deoxy-6j3-azido-14j3-hydroxymorphine (69), which has propertiessimilar to those of 67 in humans and is also an effective antitussive (63).

a,b

':>-53%

62 61

a

64

67

6865 66

Scheme 3-10. Reagents: (top): (a) methylenetriphenylphosphorance, (b) acid; (bottom):(a) LiCI, DMF, 40°C, (b) DMF, 120"C.

with weak nucleophiles by an S.l' mechanism [e.g., chloride can givea-chlorocodide (64)] and with more powerful nucleophiles by an S.lmechanism accompanied by retention of configuration (Scheme 3-10).Removal of the methoxyl methyl generates the a.chloromorphide andj3-chloromorphide analogs of 64 and 65, respectively. The a-chloro-morphide is about 15 times more potent than morphine but is considerablymore toxic, while the j3-chloromorphide is equipotent (58).

An exciting extension of this work is the displacement of the 6a-trillate with 18F to provide ligands in both the agonist and antagonistseries suitable for positron emission tomography (PET) (265). An[18F]analog of naltrexone (ef. Section II,A,7) has been used to visualize

70

69

71 (X N-NH2)

72 (X 0)

73 (X Nt2)

Dihydromorphinone (70) is readily available from morphine by reduc.tion and oxidation, or alternatively by a novel acid-catalyzed rearrange-ment of the allylic alcohol to the enol ether and subsequent tautomeri-

66 3 Synthesis of Morphine. Codeine, and Related Alkaloids II The Structure-Activity Relationships of Morphine and Related Compounds 67

zation to the 6-ketone (64). With the wide variety of phosphorus and sulfurylids now available, it is surprising that more use of them has not beenmade to introduce substituted methylene groups at C-6. A carbethoxy-methylene group introduced at C-6 in the antagonist morphine series wasdisappointing in its biological properties (65). However, these a, 13-unsaturated compounds are interesting because they possess the potentialfor irreversible receptor binding by 1,4-conjugate addition to the acrylateester group.

Another approach used to create irreversibly binding receptor ligands isto prepare the hydrazone of oxymorphone. This simple derivative (71),readily prepared by the reaction of excess oxymorphone with hydrazine,when given in vivo produced a significant inhibition of receptor binding forover 24 hours despite extensive washing of the brain membrane homo-genates. The parent oxymorphone (72) had no effect after this time period.Significantly, 24 hours after in vivo administration of 71, analgesia was stilldemonstrable in mice using the tail flick assay, while oxymorphone (72)analgesia had ceased. The mechanism for the long-lasting effects isunknown, since no evidence of covalent bonding was demonstrated (66a).The hydrazone exists as a mixture of syn and anti isomers (66b). Sub-sequently, it was found that the hydrazones comprising 71 readily andrapidly disproportionate to the azine (73) in weak acid (67). The azine,oxymorphazine (73), is 20-40 times more potent than the correspondinghydrazone while retaining the same long-lasting effects. Although covalentbinding to the opiate receptor may be possible for the azines, the potentialfor the noncovalently bound drug to dissociate very slowly has beennoted. Very slow dissociation would appear to be irreversible binding ina practical sense. Since the azine (73) is a bifunctional molecule, it couldbind to two receptor sites at once, greatly enhancing the affinity andthereby decreasing the rate of dissociation.

Further studies on the occupation of two receptor sites by two morphine-based molecules covalently linked by a spacer molecule have used the6-amino group. The original method for reductive amination of a 6-ketoneyields a 1:2 mixture of the 613-and 6a-amino epimers (68). Subsequentinvestigation has yielded stereospecific synthesis of both epimers (Scheme3-11). Preparation of the iminium salt (74, R = benzyl) forces the Coringinto a boat conformation due to steric repulsion between the vicinal etheroxygen and the syn-benzyl group. With the Coring in the boat conforma-tion, hydride transfer occurs exclusively to the more accessible a-face,thereby furnishing the 6f3-isomer (75). Catalytic debenzylation then yieldsthe stereochemically pure 6f3-oxymorphamine (76). The 6a-amine (78) isprepared by stereospecific catalytic reduction of the imine (77) preparedfrom the 6-ketone (72) and benzylamine. The imine retains the energeti-

R

~

RN a d,e~ 72 --;>

oxymorphone

R

74 (R - benzyl> 77

75 (R. benzyl> 78

76 (R. HJ

Scheme 3.) J. Synthesis of the epimeric 6-amino-oxymorphones. Reagents: a. dibenzy).amine; b. sodium cyanoborohydride; c, PdjC, hydrogen;d. benzyl amine; e, sodium boro.

hydride.

cally more favorable chair conformation and therefore results in hydroge-nation on the f3-face to yield the 6a-amine (69). Solution NMR studiesindicate that in the 6a-oxymorphamine, the Coring exists in the familiarboat configuration, while in the 6f3-oxymorphamine, the Coring exists inthe chair conformation (70). Biological activity has been reported for the6-amino epimers in the narcotic antagonist series (68). Bivalent ligandswere synthesized where two molecules of (76) were linked by variable-length spacer groups consisting of succinyl-bis-oligoglycine (79). Thegreatest receptor affinity potency difference occurred when the spacercontained two glycine residues (79, n = 2). Bridging of neighboring opiatereceptors therefore occurs when the spacer group possesses a linear lengthof 18 A. On the presumption that the marked enhancement of receptoraffinity is a consequence of bridging, it is likely that the linear spacer lengthis substantially greater than the interreceptor distance, because sufficienttranslational mobility of the oxymorphamine must be required for docking

99 ~)(L

99 ~)( L)

99 00 00. ',

"I I.. · II , , . I I , I00 00 00 00 00

unoccupied singlvoccupied independentlyreceptor receptor singly occupied

receptor.A B

1 i()

99 00II

II II00 00

bridged occupiedreceptors


79 (n ~ 0-4)

to the initial receptor recognition site. Moreover, the optimal spacer lengthfor effective receptor interaction with both pharmacophores should bedependent on the relative orientation of these neighboring receptors. Bothfactors indicate that the average distance between occupied receptors isless than 18 A (71).

The increase in receptor affinity potency for bivalent ligands withneighboring receptors is a function of entropic factors, because of therestriction 'of the univalently bound bivalent ligand within the interactivevolume of the neighboring vacant receptor (Scheme 3-12). Therefore,

99II00

c"l l::: spaced bivalent ligard

Scheme 3-12. Bridging of spaced bivalent opiate ligands (according to ref. 71).


,

I

proceeding from state B to state C has to be favored over univalent bindingof a second bivalent ligand, provided the spacer length allows bridging. Inthe extreme case, a bivalent ligand with an excessively long spacer (e.g., apolymer) would be expected to possess a potency that approximates astatistical factor of 2 over the monovalent analog due to the much largeraccessible volume of the residual free pharmacophore. In the extremecase, therefore, the infinitely spaced pharmacophores function inde-pendently. The previously described qualitative picture can be understoodin terms of the Gibbs free energy equation (toGo = toHO - T toSo). Theunivalent binding of a second bivalent ligand occurs with a greater negativeentropy change (toSo) than the bridging of a univalently bound divalentligand, which has a smaller containment volume. Thus, the free energychange (toGo) in the latter case should be more negative relative to theformer one. This assumes that the enthalpy change (toHo) accompanyingthe univalent binding of two bivalent ligands does not differ substantiallyfrom that involved in the bridging of a single bivalent ligand to twoindependent neighboring receptors. With this reasonable assumption, themore favorable entropy change is responsible for potency enhancementwhen bridging can occur (71).

A successful approach in using highly selective affinity labels to investi-gate opioid receptors utilizes the principle of recognition site-directedcovalent association, which was pioneered by Baker (72). In theory, highselectivity is achieved because two recognition processes are required forcovalent bonding: (a) the primary recognition process, which is reflectedby the affinity of the ligand for the receptor, and (b) the second recognitionstep, which involves the alignment of the electrophilic portion of thereversibly bound ligand with a proximal receptor nucleophile. It is thesecondary recognition step that is important for irreversible labelinginasmuch as covalent bonding will not occur if the electrophilic center ofthe ligand and the receptor nucleophile are not in the appropriaterelationship to one another. An attractive aspect of this approach, whichrequires two recognition steps that lead to covalent bonding, is that, intheory, extremely high selectivity can be achieved provided that theelectrophile exhibits selectivity in its choice of nucleophiles (73).

In one of the first investigations of this theory, oxymorphone (72) wasconverted into its nitrogen mustard derivative, j3-chlorooxymorphamine(80) (74). In the guinea pig ileum, 80 was equipotent to morphine.However, unlike morphine, this agonist effect could not be reversed bymembrane washing or naloxone treatment. lntracerebroventricular (icv)administration to mice resulted in a fourfold increase in the duration ofanalgesia compared to oxymorphone (75). Other in vivo results wereequivocal, but more clear-cut results were obtained with the narcoticantagonist derivative, j3-chlornaltrexamine (81).

HO N (CH2CH2Cl>2

~~C1CH2CH2

80 (R CH3) 82

81 (RCH2-<1

70 T3 Synthesis of Morphine, Codeine, and Related Alkaloids

83 (R

84 (R

Chlornaltrexamine (81) produced ultralong narcotic antagonism(2:3 days) to morphine analgesia in mice after a single icv administration.In contrast, reversible narcotic antagonists, such as naltrexone, preventmorphine-induced analgesia for less than 2 hours. In agreement with thelong duration of action of 81, a single icv dose protected against morphine-induced physical dependence for 72 hours. Corresponding in vitro studieson the effect of 81 on the guinea pig ileum also demonstrated a blockade ofthe response to morphine that is not reversible either by washing or bysubsequent morphine treatment (74).

These in vitro and in vivo data suggest that chlornaltrexamine exerts itssustained antagonistic effect by alkylating opioid receptor nucleophiles.Since this compound is highly reactive toward nucleophilic reagents, itpresumably reacts with receptor nucleophiles via its aziridinium ion (82).

An affinity label that contains a highly reactive electrophile, such as 81,would not be expected to be able to discriminate between opioid receptorsubtypes in the second recognition step because it would possess the


potential to react with a range of weak 10 strong receptor nucleophilesanywhere within its accessible steric volume. Indeed, chlornaltrexamineblocks the effect of both morphine and ethylketazocine, !J.and K agonists,respectively, on the guinea pig ileum. Irreversible antagonism of en-kephalin activity in the mouse vas deferens indicates that 8 receptors areblocked as well (76). This observation led to the development of moreselective irreversible ligands by modifying the reactivity of ligand electro-philicity.

Among the several different electrophilic groups attached to the C-6amine, the fumarate ester appears to be the best in terms of opiate receptorsubtype selectivity. The naltrexone derivative has been named J3-funal-trexamine (83) and the oxymorphone analog J3-fuoxymorphamine (84)(77). The pharmacological properties of both, using the guinea pig ileum,are significantly different from those of their nitrogen mustard counter-parts, 80 and 81. Both possess agonistic properties that can be terminatedby either naloxone or membrane washing. Comparison of receptor affini-ties indicates that 83 is about five times more potent than 84, which isequipotent with morphine. The reversible agonistic effect appears to bemediated by different receptors. The agonistic activity of 83 resembles thatof the mixed agonist-antagonists, while 84 appears to be a pure agonist. Aremarkable feature of the action of 83 is that after repeated washings of theguinea pig ileum to remove noncovalently bonded 83, the response of themuscle strip to morphine is completely inhibited. It appears that thecovalently mediated, irreversible antagonism of 83 in the preparation(presumably K receptors) is completely resistant to alkylation by 83,despite the fact that it mediates its agonistic effect through these receptors.Apparently, there are no sufficiently reactive nucleophiles, such as cysteinesulfhydryl groups, in the accessible steric volume of the 83 electrophiliccenter to add irreversibly in a Michael fashion. The in vivo results areconsistent with irreversible binding. Subcutaneous injection of 83 is able toantagonize the effects of morphine for 4 days, as measured by the tail flickassay.

The importance of stereochemistry at C-6 in opiate ligands has beeninvestigated with a series of electrophiles in both the 6" and 613configurations (78). Comparison was based on the efficiency of irreversible!J.receptor blockade (Table 3-4). The data illustrate the importance of thesecond recognition step and of covalent bonding, since only the 613isomers irreversibly blocked !J.receptors and neither of the isomeric seriesaffected the K receptors. The ligands with the 6" stereochemistryappeared to interact with the same receptors as the 613series, however,since the" isomer of 83 could protect against the irreversible effects of 83.Since both the" and 13isomers listed in Table 3-4 are potent reversible

R C-6 Configuration

NHCOC ICC02CH3 a

HCOC CCC02CH3

{3(83)

a{3

NHCOCH=CH2 a{3

NHCOCH2I a{3

N=C=S a{3

N(CH2CH2Clh a{3(81)


Table 3-4

Irreversible Effect of Affinity Labels on Morphine and Nalorphine

IC50 Ratio (treated/control)

Morphine Nalorphine b

1.2 0.96.0 1.30.95 0.51.5 J.01.2 0.81.9 1.11.0 1.22.4 1.21.3 0.86.9 1.5Irreversible agonist

28.5 28.9

;>90-93%overall

85

Scheme 3-13. The preparation of normorphine. Reagents: (a) phenyl chloroformate,potassium bicarbonate; (b) 95% hydrazine, allyl alcohol, nitrogen stream.

\involved the use o~ benzyl, ethyl, and methyl chloroformate (81). Thesewere eventually replaced by phenyl chloroformate, since the intermediatecarbamate formed with this reagent has proved easier to hydrolyze (82).Ethyl azodicarboxylate has been used to demethylate various 6-esterderivatives of morphine and codeine in reasonable yield (83). Normor-phine has been prepared from its 2,2,2-trichloroethyl carbamate in a 75%yield (84). The current method of choice utilizes an improved phenylchloroform ate method (85) that avoids the contamination of the normor-phine with dihydromorphine, formed by diimide reduction during thehydrolysis of the carbamate with hydrazine (Scheme 3-13). Norheroin (86)is prepared directly from normorphine using acid-catalyzed acetylationwith acetic anhydride (86), while 6-acetyl normorphine (87) is preparedfrom 3,N-bis(tert-butoxycarbonyl) normorphine, which is synthesized fromnormorphine and tert-butylazidoformate (86).

Biologically, the interest in normorphine came from the hypothesis thatthe analgesia produced by morphine may be mediated by metabolicdemethylation (264). The analgesic effectiveness of normorphine relativeto that of morphine varies considerably by species and route of administra-tion. By icv administration in mice, normorphine is equipotent withmorphine in accordance with its in vitro receptor affinity (87). However, itis only about 0.10-0.15 times as active as morphine by subcutaneous (sc) or

agonists in the guinea pig ileum, a deficient secondary recognition steprather than a poor primary association must be responsible for the inabilityof the 6a isomers to alkyl ate opiate receptors.

7. Substitution at Nitrogen The replacement of the N-methyl group inmorphine brings about quantitative ,and, much more significantly, qualita-tive changes in SAR, yielding compounds that are potent agonists,antagonists, and mixed agonist-antagonists. Although substitution atnitrogen in the opiates is hardly new, the importance of the work early inthis century was not recognized until the morphine antagonist properties ofN-allylnormorphine (nalorphine) were discovered in the early 1940s (79).This led to a more systematic study of the effects of substitution at theamino group of morphine.

The simplest derivative is normorphine (85), which is the startingmaterial for most N-substituted derivatives. A wide variety of procedureshas been used to effect this demethylation, including the classic von Braunreaction, utilizing cyanogen bromide (80). Subsequent improvements have

"f


...

86 (norheroin, Rl = R2 eOCH3)

87 (R1 = H, R2 = COCH3)

88

89

intraperitoneal (ip) administration (88). In dogs, normorphine is equipo-tent by intravenous (iv) administration (89), and, in humans, 0.25 times asactive by sc administration (90). Normorphine maintains the addictionprofile in addicts, and cessation of treatment after chronic administrationresults in withdrawal symptoms that are similar to but somewhat milderthan those of morphine (91). In addicts, single doses of 85 cause lesssedation, temperature depression, respiratory depression, and pupil con-striction than equivalent doses of morphine (91). Norheroin (86) and6-acetylnormorphine (87) have been tested only subcutaneously for cen-trally mediated analgesia in mice using the hot plate assay (86). In thisassay, 86 and 87 are very much alike and possess approximately 0.05 timesthe potency of their N-methyl derivatives. The secondary amines in thenor-series appear to be too polar to allow facile transport into the CNSeven when their hydrophilic hydroxyl groups are esterified, indicating thattransport phenomena rather than a lack of intrinsic activity is responsiblefor their low analgesic potency.

Other simple conversions of the amino group are oxidation to theN-oxide and quaternization. The N-oxide (88), a metabolite, is essentiallyinactive as an analgesic (92). Quaternary salts of opiates have beeninvestigated because of the interest in developing opiate agonists andantagonists that act peripherally and are excluded from the CNS. N-Methylmorphine (89), originally synthesized in 1868 (93), is active in the


acetic acid-induced writhing test, indicating peripheral analgesic activity,but is inactive in the hot plate assay, indicating central activity (94).However, the quaternary salts, when given systemically, have curare-likeactivity, causing neuromuscular paralysis, while on icv administration, 89 isanalgesic and equipotent to morphine (95a). Obviously, the completelyionized quarternary salt is excluded from the CNS, but metabolic N-demethylation can occur, producing morphine that readily penetrates theCNS. Morphinomimetic effects can then occur if a sufficient time course isused for testing. The individual diastereomers of ~-alkyl morphine haveanalgesic activity by both icv and sc administration. The N-cyclopropylmethylmorphine diastereomer, p.ossessing ~n a~ial ~-~ethylgroup, has moderate mixed agonist-antagomst propertIes with sIgmficantCNS penetration (95b).

Replacement of the methyl group of morphine with other organicresidues became significant following the description of the antagonisticproperties of N-allylnormorphine (nalorphine) (96-98), although the firstnarcotic antagonist, N-allylnorcodeine, was prepared in 1915 (99,100).Nalorphine (90) is a morphine antagonist, which although lacking analgesicproperties in ~nimals, is an effective analgesic in humans,. being comp~ra-ble to morphine (101). It was initially used as an antIdote for opIateoverdose; it wa~;also used in combination with morphine in an attempt toattain analgesia ~ithout respiratory depression. However, it has respiratorydepressant acti~ity and also produces intense dysphori~ and psychoto-mimetic effects. In addition, nalorphine produces a physIcal dependencedifferent from that observed with morphine (102). These side effects madenalorphine clinically unacceptable as an analgesic. .

The antagonist properties of nalorphine have prompted the synthesIsand biological examination of other varients of N-substitution in morphine(103-105). Extending the nitrogen substitution by only one methyl.enegroup to the N-ethyl derivative (Table 3-5) drastically reduces morph~n~-mimetic activity and reveals antagonistic properties. The 3-carbon cham ISoptimal for morphine antagonism, with the n-propyl derivative being ~spotent an antagonist as nalorphine (90). Interestingly, the acetylemcpropargyl derivative has very little activity in either direction. The .N-isopropyl group restores weak analgesic activity and potentiates morphmeeffects in the antagonism test. Lengthening the alkyl chain to n-butyl,n-pentyl, and n-hexyl restores analgesic properties and eliminates antago-nism, while branching these side chains gives inactive compounds. TheN- hen lethyl roup gives a compound with substantially enhanced~nalgesic act~ty.. ISresult has fores a 0:ved the e~tenslve wo~k that hassince been done on N-phenylalkyl synthetIc analgesIcs. SaturatIOn of t?earomatic ring reduces the analgesic potency by a factor of 20, WhIleconversion to the phenacyl derivative destroys analgesic potency.

HO

Antagonistic AnalgesicR Potency" Potencyb

91 CH2CH=CH2 (naloxone) 7-10 092 CH2CH=C(CH3h (nalmexone) 0.5 0.3

/CH293 CH2-CH"" I (naltrexone) 17 0

CH2/CH,

96 ."" 5CH2-CH"" /CH2

CH2

98 CH~D R-configuration 0.2 25

99 I 0S-c(mfiguration 0.2 0

a Relative to nalorphine (90) = 1.0.b Relative to morphine = 1.0.

table 3-5

3 Synthesis of Morphine, Codeine, and Related Alkaloids

Table 3-6

76 II The Structure-Activity Relationships of Morphine and Related Compounds 77

The Effect of N-Substitution on Morphine Analgesia Oxymorphone-Based Antagonists

RRelative Analgesic

Potency"Relative Morphine

Antagonist Potency

CH3 (morphine)CH2CH3CH2CH=CH2(90) (nalorphine)CH2C==CHCH2CH2CH3CH(CH3h(CH2hCH3CH2CH(CH3h(CH2)4CH3(CH2)sCH3CH2C6HsCH2CH2-c-C6H IICH2CH2.C~sCH2COC6Hs(CH2hCN

1.0<1.0<0.1<0.1

o<0.1<0.1

o0.70.7

<0.10.36.1.

<0.10.3<

o<0.1

1.0<0.005

1.0Potentiatesb

<0.1<0.1

Potentiateso

Potentiatesooo

<0.01

" Tail flick test in ratsb Compound potentiates the action of morphine.c Refcrence 106.

The activity trends observed in the normorphine series has led to theintroduction of various N-substituents in other morphine alkaloids thathave shown enhanced analgesic potencies compared to morphine, with thereasonable expectation that more potent antagonists would be obtained(107). Oxymorphone (72) is a narcotic analgesic approximately 10 times aspotent as morphine. Direct alkylation of noroxymorphone with allylbromide yields naloxone (91) (108). Naloxone is a potent narcotic antago-nist, being approximately 7-10 times as active as nalorphine (90) (Table3-6), while demonstrating no agonist activity either in the mouse hot plateor writhing tests (109) or in humans (110). Furthermore, naloxonecompletely antagonizes the analgesic activity of mixed agonist-antagonistssuch as nalorphine (/11). The antagonistic without agonistic effects ofnaloxone have been confirmed in humans. Naloxone antagonizes the

respiratory depression produced by oxymorphone but does not producerespiratory or circulatory effects of its own (112). Further studies inhumans confirm the lack of dysphoric agonist effects such as the psychoto-mimetic reaction and sedation (113). Naloxone has an extremely shortduration of action, whiCh makes it very suitable for the treatment of acutenarcoticism but not for blocking the euphoric effects of opiates in addicts.The (+ )-enantiomer of naloxone has been synthesized and has only 10-3 to10-4 times the activity of (- )-naloxone (267).

Introduction of a dimethylallyl group into noroxymorphone gives nalme-xone (92), which, through the simple addition of the two vinyl methylgroups, yields a mixed agonist-antagonist (114). Nalmexone is approx-imately one-half as potent as nalorphine (90) as an antagonist and aboutone-third as active as morphine as an agonist. As part of the continuingsearch for potent, long-acting antagonists for long-term opiate receptorblockade in addicts, the cyclopropylmethyl group has been introduced into

78 3 Synthesis of Morphine. Codeine, and Related Alkaloids II The Structure-Activity Relationships of Morphine and Related Compounds79

the noroxymorphone molecule, yielding naltrexone (93) (115,116). Naltre-xone has been approved for use in the United States for addicts who havebeen withdrawn from opiate addiction and are in the process of rehabilita-tion. Naltrexone is several times more potent than naloxone and has amuch longer duration of action. The cyclopropyl group in 93 protectsagainst hepatic degradation during the first pass through the liver (115).Naltrexone is 17 times more potent than nalorphine in producing absti-nence symptoms in opiate-dependent patients (117). Animal studiesindicated that 93 has an opiate antagonist potency 40 times that ofnalorphine (90) and 2-3 times that of naloxone (91) (118). The potencydifference is not large enough to explain the 20- to 30-fold difference seenin the comparison of naltrexone to naloxone with respect to duration ofaction and human dosage (119). The difference, therefore, is due todifferent metabolic pathways. Naloxone is inactivated in humans primarilyby hepatic conjugation to form glucuronides that do not readily penetratethe blood-brain barrier (120). Naltrexone, although also conjugated, isreduced primarily to 6,8-naltrexol (94), an active metabolite, which doescross the blood-brain barrier (121).

Chemically, a wide variety of reducing agents give the 6a-naltrexolepimer (95). The 6,8 alcohol can be formed by reduction with formamidinesulfinic acid (Scheme 3-14) (122,123). Biologically, 6,8-naltrexol (94) hasopiate antagonist activity that is 2-8% that of its parent, naltrexone(121,124), without demonstrable analgesic activity (123). On the otherhand, 6a-naltrexol (95) behaves as a mixed agonist-antagonist (123).

Expansion of the cyclopropyl ring of naltrexone gives the cyclobutyl-methyl analog (96). The compound is reported to be a mixed agonist-antagonist with approximately five times the potency of nalorphine andequivalent potency to morphine (Table 3-6) (125). Reduction of 96 yieldsthe 6a-a1cohol, nalbuphine (97). The reported syntheses of nalbuphine arepresented in Scheme 3-15 and are illustrative of the various methods forproducing N-substituted normorphine derivatives (125). As an analgesic,nalbuphine has four to five times the potency of morphine in the mousewrithing test but is very weak in the hot plate. In humans, 97 has beenfound to be slightly less potent than morphine, but with a marginally longerduration of action (126).

As previously indicated, replacement of the N-methyl group in mor-phine alkaloids generates a spectrum of activities from pure agonismthrough pure antagonism. An example of the subtleties inherent in thisregion of the molecule is demonstrated by the tetrahydrofurylmethylenediastereomers 98 and 99. The R-diastereomer (98) is a mixed agonist-antagonist possessing 25 times the potency of morphine in the mousewrithing assay and having the ability to suppress morphine abstinence in

93

a b

95 94Scheme 3-14. Reagents: (a) lithium tri-sec-butylborohydride; (b) formamidine sulfinic

acid.

pa~~. The S-diastereomer (99), on the other hand, is a pure antagonist with0.2 times the activity of nalorphine and no agonist properties (Table 3-6)(127).

B. Insertion of Substituents in Nonfunctionalized Areas

While manipulation of functional groups in the morphine molecule wasundertaken initially to determine general SAR, the introduction of substi-tuents into nonfunctionalized portions was done secondarily to look atspecific effects on a given opiate derivative's biological activity. On thewhole, these substituent introductions have resulted only in quantitativedifferences in analgesic activity when compared to the parent molecule.

1. Substituellts ill the AromaticA-Rillg An intact A-ring is, in general,essential for analgesic activity in morphine-based molecules. Substitutionin this ring results in reduced analgesic activity. The I-chloro and I-bromocodeine derivatives (100), as well as the I-acetyl compound (101), have

a

~CH30 OH CH30HO

noroxymorphone~100

(R = Cl, Br) 21 (R H, dihydrocodeinone)

101 (R = CH3CO) 103 (R CH2Cl)

102 (R = F) 104 (R CH3)

c d

H OH

~b---7

HO HO OH

80 3 Synthesis of Morphine, Codeine, and Related Alkaloids II The Structure-Activity Relations~ips of Morphine and Related Compounds 81

96 97nalbuphine

Scheme 3-15. Synthesis of nalbuphine. Reagents: a, cyclobutane carbonyl chloride; b,sodium borohydride; c, cyclobutylmcthylene bromide; d, lithium aluminum hydride.

2..Introduction of Substituents at Position 5: The Dihydrofuran CoRing

JunctIOn Metopon (112), 5-methyldihydromorphinone, was consideredto be one o~ the best morphine drugs developed (131). It is more potentt~an morphme on oral and sc administration, produces fewer side effectslIke nausea and vomiting, and is less sedating. Physical dependencedevelops less rapidly and is less severe than with morphine (132). Its use,however, has been restricted by its lengthy, difficult, and expensivesynthesis.

The synthesis (Scheme 3-16) of 112 is interesting in that it involves adirect ~isplacement at an allylic carbon by a grignard reagent. ThesynthesIs starts from the readily available thebaine (106) (133), which ish~drogenated to the enol ether of dihydrocodeinone (107). Reaction of 107w~th methyl ?rignard results in displacement of the allylic oxygen at C-5with concomitant cleavage of the dihydrofuran ring. The reason for thisunus.ual reaction is twofold: (a) coordination of the allylic oxygen with theLewIs ~cid ma.gnesium iodide and (b) the fact that the leaving group is apheno~lde amon. Subsequent hydrolysis of the enol ether gives the~orphl?an ketone (108). To then rebuild the dihydrofuran ring, 108 isdlbrommated to 109 and treated with base to yield the morphine derivative

significantly diminished analgesic potency relative to codeine (128).However, the l-fluoro analog (102) is as potent as codeine, indicating thatsteric bulk factors rather than electronic effects are responsible for thedecrease in analgesic potency (129). A I-methyl group has been introducedinto dihydrocodeinone (21) by chloromethylation to the l-chloromethylderivative (103) and zinc-acid reduction to the methyl group (104). The6-ketone is subsequently reduced to give I-methyl-dihydrocodeine (105)(130).

82 3 Synthesis of Morphine, Codeine, and Related Alkaloids83

a

106 <thebaine}

c

~

OH CH3

108

a,e

~

110

II The Structure-Activity Relationships of Morphine and Related Compounds

Table 3-7

The Influence of Substituents at C-5 inDihydromorphinoneb

~

107

R Analgesic Potency.,b

HCH3 (metopon) (112)CH2CH3CH2(CH3hn-CSHII

1210.1 .0.5

109

.Measured in cats; ref. 135.b

Dihydromorphine = 0.6 dihydromorphinone.

Despite the lengthy synthetic pathways needed to introduce a simplealkyl group at C-5, a number of derivatives have been prepared. Lengthen-ing the chain at C-5 results in a steady decrease in analgesic potency. An-pentyl group in this position possesses 25% of the analgesic activity ofmetopon (112), while an isopropyl group has only 5% of the activity of themethyl derivative (Table 3-7) (136). Further manipulation of metopon byreduction to the 6a-alcohol (113) reduces the analgesic potency to 1/50th

112 (R = H, metopon)

Scheme 3-16. Synthesis of 5-methyldihydromorphinone (Metopon) from thebaine. Rea-gents: a, catalytic hydrogenation; b. methyl grignard; c. bromination; d, base; e, demethyla-tion.

\110). The residual bromine is removed by catalytic hydrogenation,forming 5-methyldihydrocodeinone (111). Demethylation at C-3 thenyields metopon (112) (132,134,135). It was reported that treatment ofthebaine (106) with butyl lithium at low temperature results in stereospe-cific deprotonation at C-5. Alkylation with methylfluorosulfonate gives5f3-methylthebaine, which is then converted into metopon (112), as wellas various 5-methylcodeine derivatives (135).

113

that of metopon (112) (137). A later study varied the nitrogen substitutionby introducing the strongly agonistic phenethyl group and the antagonist,producing dimethylallyl and cyclopropylmethyl groups. Both the 6-ketoneand the 6a-alcohol of these derivatives have been prepared (Table 3-8).Surprisingly, not only do the agonist-enhancing groups produce active


Table 3-8

a

The Effect of C-6 and Nitrogen Substitution on 5-Methyl SubstitutedMorphine Derivatives

115

Analgesic Potency..b Antagonism

=0=0=0=0...OH

...OH

CH3 (metopon)H(CHzhC6H,CHzCH=C(CH3h(CHzhC6Hs

CHz-<1 116

1.00.28

0.250.5

0.02

No

NoNoNo

No

.Hot plate test, sc, in mice.b Morphine = 0.4 metopon.

analgesics, but the antagonist-producing groups give compounds retainingthe analgesic activity and do not demonstrate any morphine antagonism(138).

3. The Influence of Substituents at Position 7 on Analgesia As pre-viously indicated, much of the focus on the introduction of substituentsinto nonfunctionalized areas has been a classical medicinal chemicalexercise in potency enhancement. While this is partially true for the C-7region of the morphine molecule, a great impetus for substitutions hasbeen the tremendous potency enhancements found in the Diels-Alderadducts of thebaine and the related oripavine derivatives (qv). It has beenobserved empirically that in the Diels-Alder adducts, an alkyl substituentat C-7 is the most important factor in enhanced potency (139).

A methoxyl group has been introduced at C-7 using the I-bromoderivative (115) of the naturally occurring morphinan alkaloid, sinomeni-none (114) (Scheme 3-17). The 7-enol ether of 115 is brominated and thentreated with base to close the oxide bridge to the sinomenine derivative(116). Hydride reduction then reduces the 6-ketone to the 6a-alcohol andreductively removes the I-bromine to give 7-methoxycodeine (117), whichin the presence of acid regenerates sinomeninone (114). The analgesicpotency of 117 is about one-third that of codeine when administered

117(7-methoxycodeine)

:::0

CH30 OH

114(sinomeninone)

Scheme 3-17.. Synthesis of 7-methoxycodeine from sinomeninone. Reagents: a, methanol,hydr?gen chlonde; b,. bromine, acetic acid, then sodium hydroxide; c, lithium aluminumhydnde; d, hydrochlonc acid.

subcutaneously in the hot plate test and is equivalent to codeine whengiven orally. Since 117 is unstable to acid, the product sinomeninone (114)was tested for analgesic activity. While it was active parenterally, it was notactive orally, indicating that the oral analgesic activity of 117 is not due toits conversion to 114 (140).

The introduction of 7-alkyl groups.has been accomplished in a variety ofways, none of which is a straightforward alkylation process. In contrast tothe reaction of thebaine (106) with methyl grignard, ultimately forming

86 3 Synthesis of Morphine, Codeine, and Related Alkaloids87

a---7

106(thebaine)

cCH3 ~

or d

118

II The Structure-Activity Relationships of Morphine and Related Compounds

21 122

e,f,g~

CH30 OH

119 R = H, CH3

125R = H (12 3), OH ( 12 4) ,alkyl, phenyl, acetyl

Scheme 3-19. Preparation of 7a-substituted morphinones. Reagents: (a) dimethyl forma-mide dimethylacetal; (b) hydrogenation under various conditions; (c) organo-lithium rea-gents.

7-O'-methyl compounds (121) (142,143a). An alternative approach(Scheme 3-19) is the reaction of dihydrocodeinone (21) with dimethylfor-mamide acetal to give the vinylogous amide (122), which can be hydroge-nated to the 7O'-methyl (123) or the 7a-hydroxymethylene (124). Other7-substituents could be introduced by the reaction of 122 with organo-lithium reagents to give 125 followed by hydrogenation. These reactionshave also been applied in the 1413-hydroxy series (Scheme 3-19) (142).

The effects of these substitutions on analgesic potency are presented inTable 3-9. These data indicate that the introduction of a methyl group intothe 7a position in the N-methyl compounds increases the analgesicpotency relative to codeine but is equivalent to that of the unsubstitutedcodeinone. Increasing the size of the group in the 7a position to largerthan a methyl causes a drop in potency, as does the incorporation offunctionalized side chains. In the N-cycloalkylmethylene compounds,methyl substitution at the 70' position increases the analgesic potency overthat of morphine but reduces antagonist activity. Further introduction of

n = 2,3

Scheme 3-18. Synthesis of 7-methyldihydromorphinone derivatives from thebaine. Re-agents: a, lithium dimethylcuprate; b, acid; c, catalytic hydrogenation (for R = H); d, excess

lithium dimethylcuprate (for R = CH3); e, von Braun reaction; f, N-alkylation withcycloalkylmethyl bromides; g, bromine, acetic acid, then sodium hydroxide; h, borontribromide.

metopon (112), the reaction with lithium dimethy1cuprate gives a 7-methylmorphinan (118) (Scheme 3-18) (141). Hydrogenation of the enonein 118 gives the 7O'-methyl morphinan; reaction with lithium dimethy1cu-prate gives the 7a-813-dimethylmorphinan (119). Because of the instabil-ity of 7-methylcodeine to acid, the N-methyl group is removed and theresultant nor-compound is alkylated with cycloalkylmethylene halidesprior to ring closure to the dihydrofuran (120) (135). Removal of thecodeinone 3-methoxy methyl group with boron tribromide then yields the

88

Table 3-9


The Effects of 7-Substitution on Analgesia

Analgesia

TailOther Writhinga Flickb Antagonism'

CH3 CH3CH3 CH2CH3CH2 (CH2).CH3CH3 CH2C(CH3hCH3 CH2C6HsCH3 CH20HH CH3H CH3H CH3H CH3H CH3H CH3

H CH3H CH)H CH3H CH)H CH3H CH)H CH2-c-yHsCH3 CH2-c-C3HsH CH2-c-C.H7CH3 CH2-c-C4H7H CH2-c-yHsH CH2-c-C.H7

14-0H14-0H

3.8d2.20.5I

<0.41.02.0'I2.70.1I0.6

0.611.7

<0.10.4

280.2

a Mouse, sc.bRat, sc.,

Rat tail flick, sc.d Relative to codeine = 1..Relative to morphine = 1.1 Relative to nalorphine = 1 (Table 3-5).

an 8f3 methyl group almost eliminates analgesic activity without producingremarkable effects on antinociceptive activity. Introduction of a 14f3hydroxyl group with a 7a methyl yields an antagonist about twice as potentas naltrexone (93) (Table 3-6). The conclusion that was drawn fromthese data is that introduction of a 7a methyl group into the N-cycloalkyl-methylene opiates does not result in agents that have potent mixedagonist-antagonist properties (142).

Geminal dimethyl groups have been introduced at C-7 through a novelcrossed aldol-Cannizzaro reaction on dihydrocodeinone (21), which resultsin reduction of the ketone to the 6f3-a1cohol and introduction of the7,7-bis-hydroxymethylene group (126) (Scheme 3-20) (143b,144). Selec-


b,c--=JI.

d

21 126

e?

CH30127 128

R H, CH3, CH2CH3

Scheme 3-20. Synthesis of 7,7-dimethyl-dihydromorphone and codeine derivatives. Rea-gents: (a) formaldehyde, calcium hydroxide; (b) p-toluene sulfonyl chloride, pyridine; (c)lithium triethylborohydride; (d) dimethyl sulfoxide, trifluoroacetic anhydride; (e) sodiumborohydride.

tive tosylation of the C-7 substituent followed by hydride reduction givesthe 7,7-dimethyl-6f3-hydroxyl compound that is oxidized to the ketone(127) and reduction to the 7,7 -dimethyl-dihydrocodeine (128). Additionalsubstitution can be introduced at C-8, and the N-substituent can beconverted to cyclopropylmethylene and the 3-methoxyl converted to thefree phenolic hydroxyl, as shown in Scheme 3-18 (144). The biologicalresults of these substitutions are shown in Table 3-10. In the dihydro-codeinone series, a geminal dimethyl group increases the analgesic potencyover that of codeine but retains approximately equivalent potency todihydrocodeinone in both the writhing and tail flick assays. In thedihydromorphinone series, with a free 3-phenolic hydroxyl, the 7,7-dimethyl analogs possess enhanced analgesic potency over both morphineand dihydromorphinone (see Table 3-3). With an N-cyclopropylmethyleneand 7,7-dimethyl groups, the compounds are pure antagonists devoid ofagonist activity (144). In general, the introduction of a 7,7-dimethyl groupcan enhance the analgesic activity of morphine-based opiates, but thiseffect depends on the specific groups at C-8 and on the amine nitrogen. Theeffects are not great compared to those that can be achieved by othersubstitutions.

R1 R2 R)

CH3 H CH)CH3 CH) CH3CH) CHzCH) CH)CH) H CH)H H CH)H CH2CH) CH)H H CH2-c-C)H~H CH) CH2-c-C)H~H CH2CH) CHz-c-C)H~

Analgesia

Writhing" Tail Flick b Antagonist C

2.6.1 7.74.1 182.3 5.40.8

11' 19.53.5 31I 2.1'I 6.5I 1.0

OH

R1 R2 R) Analgesic Potency"

CH) H CH) 3.SbCH) CH2CH) CH) O.SCH) C6H~ CH) 370CH) CH2C6Hs CH) 26CH) (CHzhC6H~ CH) 735CH) (CH2hC6H~ CH) 4.4H (CHzhC6Hs CH) 700"CH3 (CHzhC6Hs CH2-c-C3Hs SObH CHZC6HS CH2-c-~Hs 4.5"

90 3 Synthesis of Morphine, Codeine, and Related Alkaloids II The Structure-Activity Relations~ips of Morphine and Related Compounds 91

Table 3-10

a,b

---7c

7,7-Dialkyl Codeinone and Morphinone Derivatives

Other

H£CH-CH=CH-C6HS

"'CH20H d~

CH30

Scheme 3-21. Reagents: (a) acetone, acid; (b) Swern oxidation; (c) cinnamyl Wittig; (d)catalytic hydrogenation.

OH

6a-OH

Table 3-11

7a-Hydroxymethylene Morphine and Codeine Derivatives

A series of 7-acyl derivatives of dihydrocodeinone (21) and dihydromor-phi none were prepared by acylation of the morpholine enamine of 21 andsubsequent boron tribromide de methylation (145). Of the ,B-diketonesthus prepared, the 7-hexanoyl derivative (129) is the most interesting,possessing one-fourth the analgesic potency of dihydromorphinone (70)(see Table 3-3), wth very weak antagonist properties (145).

The most interesting results in this series occur when a lipophilic 7,Bsubstituent is introduced. The required stereochemical configuration wasprepared as illustrated in Scheme 3-21. Because of the method of synthesis,all the derivatives prepared contained a 6,B-hydroxyl instead of thenaturally occurring 6a, and a 7a hydroxymethylene group (146). Thebiological results are presented in Table 3-11. Introduction of a 7,B alkylgroup has little effect in the dihydrocodeine series. However, introductionof a phenethyl group increases the analgesic potency to 370 times that ofcodeine, while a phenylbutyl has over 700 times codeine's potency.

" Mouse, sc.bRat, sc.e Tail flick rat. sc..I Relative to codeine = I.e Relative to morphine = 1.f

Relative to nalorphine = ] (Table 3-5).

U Mouse writhing assay.b Relative to codeine = I.

" Relative to morphine = 1 (codeine/morphine = 5).

Curiously, the phenylpropyl group confers less than 50% of the activity ofthe phenyl butyl. Above four methylene groups, the analgesic potencyrapidly falls off. Similar results have been obtained in the dihydromorphineseries. When the N-methyl group is replaced by a cyc1opropylmethylene,


potent analgesic activity is retained in the codeine analogs, but themorphine analogs are only marginally better than morphine itself. Narcoticantagonism has not been demonstrated for these compounds (146).

Through a complex series of steps, 130, which contains the requisite6a-hydroxyl and a 7a methyl group in place of the previously preparedhydroxymethylene, was synthesized. This compound (130) has about 20times the potency of codeine but is about one-half as active as itshydroxymethylene analog. Oxidation to the 6-ketone formed thecodeinone (131) and subsequently the morphinone (132) derivatives.Although both of these contain the N-cyclopropylmethylene group charac-teristic of the antagonists, they are equipotent to dihydrocodeinone (21)and dihydromorphinone (70) respectively (146). The syntheses of the much

129

(CH2)4C6HS/

"CH3

RO

130131

132

(R

(R

II The Structure-Activity Relationship~ of Morphine and Related Compounds 93

52

+

CH30

Scheme 3.22. Synthesis of 8-ethyldihydrocodeinones. Reagent: (a) lithium diethyl su-

prate.

more interesting compounds (133), containing the N-methyl group in placeof the N-cyclopropylmethylene in 131 and 132, have been reported, withno indication of biological activity (147).

4. C-B Substituents Impetus for the investigation of the effects ofsubstituents at position 8 has stemmed from the high analgesic potencies ofthe Diels-Alder adducts of thebaine (Section III). In an attempt to explainthe potent analgesic activity of this series of compounds, the existence of alipophilic site on the opiate receptor surface was hypothesized (148). Thisputative site would interact with the alkyl portion of the tertiary alcohol-containing side chain of the C-ring. Modeling indicated that this lipophilicreceptor site was proximate to both C-7 and C-8 of morphine.

Substituents are readily introduced at C-8 by l,4-conjugate addition oflithium dialkyl cuprates to codeinone (52), giving, as the major product,8{3-alkyl-dihydrocodeinones (149). The 8a epimers are also formed inlow yield (150). The synthesis of the 8-ethyl epimers is illustrated inScheme 3-22. A series of 8-acyl compounds has been prepared byl,4-conjugate addition of acyl anion equivalents. The 8-acyl compoundsare of interest because of their ease of conversion to the tertiary alcohols.Biologically, a wide range of 8{3substituted compounds with unsaturated,branched, or large straight chain alkyl groups, together with acyl andtertiary alcohols, have been disappointingly less active as analgesics, bothcentrally and peripherally, than dihydrocodeinone (149). The 8{3-methyl

--94 3 Synthesis of Morphine, Codeine, and Related Alkaloids

134 (R = CH3)

135 (R = CH2CH3)

136(codorphone)

HO

137

(134) and ethyl (135) dihydromorphinone derivatives are equipotent withthe unsubstituted parent. Because ot this activity, N-cyclopropylmethylderivatives have been prepared in both the morphinone and codeinoneseries. The most interesting compound to come out of the C-8 substitutedopiates is codorphone (136), which has a mixed agonist-antagonist profileand has undergone clinical evaluation (149). Surprisingly, introduction ofeither a heteroatom or a halogenated or otherwise functionalized sidechain effectively eliminates analgesic activity in the 8f3 substituted dihy-drocodeinone series (151). The 14f3-hydroxy-8-substituted compoundshave also been synthesized, but analgesia results have not been reported(152).

5. Natural and Unnatural Substituents at C-10 Position 10 on mor-phine has been relatively little investigated. However, since C-lD isbenzylic on an electron-rich ring, it should be readily oxidatized throughradical reactions. The 1O-keto compound (137) has been isolated frommorphine solution, but no indication of its biological activity is available(153). In a rare application of organometallic chemistry to the opiumalkaloids (Scheme 3-23), the chromium tricarbonyl complex of codeine(138) has been prepared and its configuration determined by X-raycrystallography. Alkylation of a protected version of this complex withmethyl iodide gives the lOf3-methyl derivative (139) after removal of the


a

~ (CO)3cr

42(codeine)

138

b,c,d,e

139 (R CH3)

140 (R H)

Scheme 3-23. Synthesis of lO-methyl morphine derivatives. Reagents: a, chromiumhexacarbonyl; b, tert-butyl dimethylsilyl chloride; c, sodium hexamethyldisilazine, methyliodide; d, pyridine; e, tetrabutyl ammonium fluoride.

chromium and deprotection. The morphine derivative 140 was preparedfrom 139 using standard methods (154). Biologically, the 1O-methylderivative in the codeine series (139) is equipotent to codeine, while thelD-methyl-morphine analog (140) is much less potent than morphine (154).

6. Thebaine-Derived Substituents at C-14 One of the earliest substi-tuents introduced into the morphine nucleus was a 14f3-hydroxyl groupthat was ultimately derived from the then rare alkaloid, thebaine. Thebain(106) occurs as a minor alkaloid in the opium poppy but is the mainalkaloid (up to 52% in the dried latex) in another poppy species, Papaverbracteatum (155). The presence of the 3-0-methyl ether in thebaine makesthis alkaloid an attractive starting material for the preparation of codeineand codeine-derived antitussives and analgesics, since the syntheses do notgo through morphine or other readily abusable substances. The 14-hydroxyl group confers a substantial increase in analgesic potency over theparent unsubstituted compound.

Chemically, a 14f3-hydroxylgroup is introduced by oxidation of the-baine with either hydrogen peroxide or peracids in organic acids (156,157).


a~

106(thebaine)

141

1

142(l4-jJ -hydroxy-

codeinone)

1

146

Scheme3-24. Synthesis of 14,6-hydroxycompounds from thebaine. Reagents: (a) hy-drogen peroxide, organic acid; (b) meta-chloroperbenzoic acid, organic acid.

Initially, the oxidation was postulated to proceed through l,4-addition ofthe elements of hydrogen peroxide to thebaine to produce the 6,14-diol(141) (Scheme 3-24), which undergoes expulsion of methanol to form14,8-hydroxycodeinone (142) (156). While l,4-addition is possible, subse-quent investigations and ancillary evidence make this direct mechanism

II The Structure-Activity Relationship,s of Morphine and Related Compounds 97

unlikely. A more likely mechanism is the epoxidation of the 8 (14)-doublebond to form the intermediate (143), which undergoes acid-catalyzed ringopening to give 144. The epoxide ring-opened intermediate (144) canproceed directly to 142 or, alternatively, can undergo water or organic acidaddition to form 145. The 8,8,14,8-diol enol ether (145) has been isolatedin good yield from the meta-chloroperbenzoic acid oxidation of thebaine ina mixture of acetic and trichloroacetic acids (158). Hydrolysis of the enolether in 145 gives the known dihydroxydihydrocodeinone derivative (146)(159). Both 145 and 146 are readily convertible into 14,8-hydroxycodeinone (142) (158). Further transformations of 142 includehydrogenation to 14,8-hydroxydihydrocodeinone (147). The classicalmethod for converting 147 into oxymorphone (72) is reaction of 147 withhot hydrobromic acid (160).

Additional evidence for initial 8,14-addition comes from nitration stud-ies of thebaine. Initially, reaction of thebaine with tetranitromethane wasreported to give 14,8-nitromorphinone (148) (161). Subsequently, whenthebaine was oxidized with dinitrogen tetroxide, 8-nitrothebaine (149) wasisolated, which is consistent only with initial formation of an 8,14-dinitroderivative (Scheme 3-25) (162).

HO OH

147(oxycodone) 150

151 (no 6,7,8)

Biologically, the effects of 14,8-hydroxyl substitution are species depen-dent. While oxycodone (147) and oxymorphone (72) have only 1.4 and 11times the potency of morphine in mice, respectively, oxymorphone has 6.7times the analgesic potency of morphine in humans, while oxycodone has apotency of 0.7 times (25,29,163,164). The 14,8-hydroxyl derivatives ofmorphine (150) and its dihydroanalog (151) are equipotent to morphine, atleast in mice (165). The 14,8-hydroxyl group in these compounds isstrongly hydrogen bonded to the amino nitrogen, which may provide areason for the potency-enhancing influence of this substitution (166). Avery interesting observation on potency SAR has been made for the estersof 14,8-hydroxycodeinone (142); instead of hydrogen-bonding effects,

a

~CH30OCH3 CH30 OCH3

106

/1


Table 3-12

n The Structure-Activity Relationship,s of Morphine and Related Compounds 99

SAR of the Esters of14-H ydroxydihydrocodeinone

R Analgesic Potency.,b

H (142)COCH3COC:zHsCOC3H7-nCOCH1CH=CHzCOC.H9-nCOCSHII-nCOC6HIJ-nCO~HwnCO~H1TnCOC11HI9-nCOCHZC6HSCO(CHz)zC6HSCOCH=CH-C6HsCOCH=CH-CH3

148 149Scheme 3-25. Reaction of thebaine with dinitrogen tetroxide. Reagent: (a) dinitrogen

tetroxide or tetranitromethane.

0.34

203030405060

5I0.03

50liS

175:!: 7531

potency may be due to partition coefficient effects (Table 3-12) (167).These derived esters are all analgesics, some with very high potencies. Theanalgesic potency rises with increasing size, peaking when R is n-hexyl andthen diminishing. The benzoyl esters are inactive but phenacyl, cinnamoyl'land related esters are up to 200 time$ as potent as morphine or 600 times aspotent as codeine (167,168). Transport factors are probably the mostimportant component of the SAR relationships here, but conformationalchanges due to non-hydrogen-bonded interactions between the 14,8 esterand the amino group may also be important.

Although the effects of a 14,8-hydroxy group have been known for along time, only recently have other substituents been introduced at thisposition. The nitro derivative (148) can be reduced with sodium borohy-dride to the 14,8-amino group, which is trapped with acetic anhydride togive the acetamido derivative, which can be demethylated with borontribromide to give the 14,8-acetamido-morphine derivative. Other substi-tuents can be introduced by the reaction of thebaine with thiocyanogen,

. Tail clip paradigm, sc, in mice.b Relative to morphine (= 1).

(SCN)z, or positive halogen. Demethylation then gives the 14,8-substi-tuted morphine and morphinone derivative (Table 3-13) (169). Theanalgesic potency of these derivatives has been determined using theguinea pig ileum with normorphine as the standard, although normorphineanalgesia is reported to be strongly species dependent (d. Section II,A,7).In this paradigm, all the 14,8-substituted codeine derivatives are extreme-ly weak. However, codeine itself is extremely weak in this assay (169,170).The analgesic potencies of all the morphine derivatives are less than that ofmorphine (169). The influence of 14,8 substituents has also been investi-gated in the naltrexone series (171).

A phenylamino group has been introduced by a 1,4-cycIo-addition ofthebaine with substituted and unsubstituted nitrosobenzene derivatives(Scheme 3-26) (172). Rearrangement of the initial hetero Diels-Alder

100

Table 3-13

3 Synthesis of Morphine, Codeine, and Related Alkaloids 101III Diels-Alder Adducts of Thebaine- - -adduct yields".Jhehydroxyamiiie (152), which can be converted to the 1413phenylamine derivative (153) with concomitant reduction of the 7(8)-double bond. Unfortunately, none of the substituted analogs are as potentas morphine when tested in the mouse writhing assay (172).

Another hetero-Diels-Alder reaction is used to prepare 14J3-aminomorphine and morphinone derivatives. Reaction of thebaine with 1,1-chloronitrosocyclohexane yields, after zinc reduction, 14-aminocodeinone

Thc Analgesic Activity of 1413-Substitutcd Morphineand Morphinone Derivatives

Analgesic Potencya,b

=0...0zCCH)... OH=0=0...OH

NOzNHCOCH)SHCIBr...OH

0.0060.60.40.50.40.8

155 156

a?

.Guinea pig ileum.b Relative to normorphine (85) = 1.

CH30 OCH3

106(thebaine)

154

(154) (173). Conversion into the 14J3-bromoacetamide derivatives 155 and156 is readily accomplished using standard methodology (174). It will berecalled that reduction of the 14J3-nitro derivative also results in thereduction of the 7(8)-double bond (169). The bromo acetamide derivativesare of interest as irre~ersible ligands (d. Section II,A,6), and both possesshigh affinity for the opiate receptor (ICso = 15 and 10 nm, respectively;morphine = 4 nm) and demonstrate irreversible binding when incubatedwith brain membranes for at least 30 minutes (174).

III. Diels- Alder Adducts of Thebaine

Thebaine (106), an alkaloid present in 0.2-0.8% in opium and a majorconstituent (90% of total alkaloid content) in Papaver bracteatum (which ismorphine free), possesses little utility commercially or medically for tworeasons: (a) its lack of the depressant and analgesic properties common to

153 152Scheme 3-26. Reaction of thebaine with nitrosobenzenes. Reagents: (a) nitrosobenzene'

(b) hydrochloric acid; (c) hydrogen. Pd/C. '

IOZ 3 Synthesis of Morphine, Codeine, and Related Alkaloids III Diels-Alder Adducts of Thebaine 103

106

157

-- - .

have been st~died extensively, along with further structural modificationsof the aromatic oxygen and piperidine nitrogen functionalities, for exam-ple, C-3 demethylation to the phenol and N-cyclopropylmethylation ofnorthebaine bases. Thus, the initial disclosure by Bentley and his col-leagues (175), the major contributors in this area, concerning ready accessto a series of Diels-Alder adducts of thebaine and related alkaloids has ledto exhaustive chemical efforts using various dienophiles and subsequenttransformations in the search for new structural types displaying a separa-tion of analgesic activity from undesired toxicity and addictive liability.Thebaine has therefore provided the raw material for new analgesicagents; its ring-C bridged derivatives, in their complexity, have beenstructural probes for the opiate receptor.

The chemistry of the Diels-Alder adducts of thebaine (106), oripavine(157), and derivatives, yielding the six-membered ring 6,14-endoethenotetrahydrothebaines and oripavines and numerous derivatives, has beenthoroughly reviewed (176,177). The highlights of this work include the C-7substituent classes of ketones, esters, alcohols, a,f3-unsaturated ketones,amin'es, nitriles, alkanes, and others, many of which not only have intrinsicvalue as potentially potent analgesics but also have value as precursors ofothe; structural types that are available through chemical transformation:modification of the C-7 substituent, 3,6-0-demethylation, reduction of the6,14-etheno bridge, removal of the C-3 oxygen functionality, substitutionin the aromatic nucleus, nitrogen demethylation and alkylation, base-and/ or acid-catalyzed rearrangement, dehydrogenation, nuclear substitu-tion, and ozonolysis. Efforts in this area are continuing; a few of theclassical examples and a sample of recent work are highlighted below.

other morphine alkaloids and (b) its expression of extreme toxicity andCNS stimulation. The value of and interest in thebaine in recent years havethus centered on the pharmacological exploitation of its transformationproducts, most notably the 6,14-endoetheno and 6,14-endoethano deriva-tives, those C-ring bridged adducts of general structural type 1581 derived

158

159

R' = R" = H, alkyl, aryl

R = CH3 Thebaine

R = H Oripavine

R H, CH3

Rl H, alkyl, halogen

R2 alkyl, substitutedor cyclo

X C2H2, C2H4y yl

= H, alkyl, ketoor carboxyl derivativeamine, alcohol

Z H, alkyl, alkenyl,carboxyl derivative

A. Ketone, Sulfone, Nitroso, Ester, and Nitrile Adducts

160

1. Synthesis Using Ethylene Dienophiles Thebaine readily undergoesDiels-Alder additions of unhindered dienophiles (176,177), various sub-stituted ethylenes (178,179) (Scheme 3-27), and nitroso compounds (180)such as nitroso-carbonyls (181-184) and -arenes (185-187). Due to thee'lectron-rich Coring, a number of Dlels-Alder reactions with otherdienophiles and molecular rearrangements of the resulting adducts havebeen investigated (188). In each case, the dienophile approaches thebainefrom the face containing the nitrogen bridge, which is the least hinderedside of the molecule. The reaction is under electronic control; unsymmet-rical dienophiles such as alkyl and aryl vinyl ketones (189), acrylic esters,or acrylonitriles (178,189) add to give only C-7 substituted 6,14-endoethenotetrahydrothebaines (Table 3-14), with classical examplesbeing thevinone (166), nepenthone (168), and ethyl thevinoate (170),

from condensation of thebaine on the exposed face of the diene systemwith a variety of dienophiles. Substituents at C-7, especially the ketonicadducts of type 159 and the secondary and tertiary alcohols of type 160,

I R, X, Y, and Z's with number superscripts are uscd throughout for substituents directlyattached to the morphine skeletal atoms; R's with prime superscripts arc used throughout forsubstituents at sites removed from the above.

Dienophile Substituents

R' R2

166° H COCH3167 H COCH2CH3

168' H COC6HS169 H C02CH3170d H C02CH2CH3171 Cl C02CH3172 Sr C02CH2CH3173 OAe C02CH2CH3174 H CN

175 CH3 CN176 Cl CN177 H S02CH3178 H S02CHCH2


/161

106

162 70',80'

163 7 IJ , 81J

1647/1,8(¥

165 7u,81J

Scheme 3-27. Diets-Alder adduct products of thebaine with ethylene dienophiles.

III Diets-Alder Adduets of 1l1ebaine 105

Table 3-14

Diels-Alder Products Formed from Thebaine and Ethylene Dienophiles/ I

-CH3

2

Thebaine

106

161

Product (in %)

<5

6100'100'70'50

lOO'75'25

lOO!

lOOt

.Thevinone. b Reference 189. C Nepenthone.d Ethyl thevinoate. 'Reference 178. ! Reference 190.

formed from methyl and phenyl vinyl ketones and ethyl acrylate, respec-tively. There is no evidence for the production of C-8 substituted com-pounds. The stereochemistry of the product is almost entirely 70' formonosubstituted ethylenes; the acrylonitrile product (174) is an exception,having considerable amount of 7{3 formation (189). Most 70: sulfonylcompounds (190) have been epimerized by treatment with hot ethanoJicsodium hydroxide, whereas other thebaine Diels-Alder adducts that havean electron-withdrawing 70'-substituent and a 7{3-hydrogen suffer base-catalyzed rearrangement.

Most of the ketone, ester, and nitrile Diels-Alder adducts of thebaineand their derivatives formed from monosubstituted or 1, I-disubstitutedethylenes have had disappointing biological activity as either analgesic

106 3 Symhesis of Morphine, Codeine, and Related Alkaloids

Table 3-15

Analgesic Activity of7a-Ketone Diels-AlderAdducts

70., R' GroupAnalgesia," Tail Pressure b

Molar Potency Ratio

HCH3CH(CH3hC6HS(CH2hCH3

0.6<1.29.00.70.03

a Reference 192. bRats, sc.< Relative to morphine = 1.0.

agonists or antagonists. A number of adducts with varying structures,however, have displayed notable pharmacological profiles, as discussedbelow, with trends being outlined by Lewis (191).

The 7a-ketonic adducts of type 161, in which R = hydrogen, methyl,isobutyl, phenyl, and octyl, have displayed analgesic potencies relative tomorphine (Table 3-15) in various protocols, namely, rat tail pressure,mouse hot plate, and mouse phenyl benzoquinone writhing. Maximumactivity resides in the isobutyl analog, which has nine times the potency ofmorphine (192). Interestingly, thevinone (166) is equipotent with mor-phine. By contrast, ethyl thevinoate (170) shows no analgesic activity up todoses of 200 mg/kg.

The sulfonyl compound 177 and certain tertiary amines, derived fromvinyl sulfone adduct 178 by treatment with secondary amines, have shownanalgesic activity in rats. Approximately 5-15 times less potent thanmorphine, compounds 177, 179, 180, and 181 have a potency similar to thatof codeine (190) (Table 3-16). I

The adducts derived from addition of aromatic nitroso compounds arevaluable intermediates to previously inaccessible analgesic 14-arylaminodihydrocodeinones (184), due to facile acid hydrolysis of theprecursor 1,2-oxazines (182) to 14-(N-hydroxyarylamino)codeinones (183)followed by catalytic reduction (193) (Scheme 3-28). Codeinones anddihydrocodeinones that have 14-alkyl or 14-alkenyl substituents are

Table 3-16

Analgesic Activity of 7a-~u)fQne_Diels-Alder Adducts

/

Analgesia,a Tail Pressureb

70., R' Group ED so (mg/kg) Potency

177179180181

CH3CH2CH32-Morpholinoethyl

2-Piperidinoethyl

23<141310

0.07d0.120.130.17

a Reference 190. bRats, ip.< ED50 of morphine = -1. 7 mg/kg.d Relative to morphine = 1.0; codeine potency = 0.2.

O=N-@X

X II - CH3 . C 1 . H

>

106 182

1.

b(

184 183

Scheme 3-28. Synthesis or 14-arylaminocodeinones using nitroso arene Diets-Alderadducts. Reagents: (a) acid; (b) catalytic hydrogenation.

108 III -Dieis-Alder Adducts of Thebaine3 Synthesis of Morphine, Codeine, and Related Alkaloids

Table 3-17

Analgesic Activity of 14-(Arylamino)eodeinones

a,b

185,186187

Analgesia a

R GroupWrithing Testb

EDso (mg/kg)

Straub Tail TestbADso (mg/kg)

-1O.5d-5>20

185186187

CH3CPM'CH3

c,d

a Reference 193. b Mice, se.e

EDso of morphine = 0.26 mg/kg.d

EDso of naloxone = 0.09 mg/kg.,CPM = cyclopropylmethyI.

-

170

isolated as rearrangement products from the 7a-ketones by first treatingthese Diels-Alder adducts with the appropriate Grignard reagent and thenrefluxing in formic acid (ct. Section III,B,3).

Of the 14-(arylamino)codeinones, only two p-fluorophenyl derivatives(185 and 186) have displayed any activity (Table 3-17). Most N-methylcompounds are only one-third to one-tenth as potent as morphine anddisplay no antagonist activities, such as 185. The N-cyclopropyl derivatives(186) have only slight antagonist activities. A 14-hydroxylamino intermedi-ate (187) has displayed an unusual mixture of agonism in the writhing assaybut not in the tail flick test, where instead antagonism and excitation occur(193).

Most 7a-substituted 6,14-endoetheno and 6,14-endoethano tetrahy-drothebaines, including ketones, esters, and alkyls, can be selectivelydemethylated. For example, ethyl thevinoate (170) is readily converted tothe corresponding oripavine (188) (Scheme 3-29) by heating an intermedi-ate C-19 ketal, formed by mild treatment with a trialkyl orthoformateester, with potassium hydroxide in diethylene glycol (194). Using the ketalderivative of esters and ketones avoids transformation to the usual

c,d

109

188

189

190

S h 3-29 C-3 and C-6 O-demeth ylation syntheses. Reagents: (a) trialkyl orthofor-e erne . . .

d (d)mate; (b) potassium hydroxide, diethylene glycol; (c) hydrogen bromide, ace lie aCI ;ethanol, hydrochloric acid.

R R1 R'

170 CH3 CH3 CH2CH3198 CH3 H CH2CH3199 H H CH2CH3200 H H (CH2)3CH3

Analgesia,"X R R1 Tail Pressure Testb

191 CzH2 CH3 CH3 Inactive193 CzH2 H CH3 1.5e

192 CzH4 CH3 CH3 0.5194 CzH4 H CH3 4.0195 CzH2 CH3 CPM' 0.18,1

lIO 3 Synthesis of Morphine, Codeine. and Related Alkaloids

base-catalyzed rearrangement products. Treatment of 170 at room temper-ature with hydrogen bromide in acetic acid yields, after reesterification, the6-0-demethyl analog (189). Prolonged treatment yields the bis-demethylcompound 190 (1~5). By analogous procedures, N-substituted demethyland bis-demethyl analogs have been prepared, some of which have shownslight but not significant antagonist activities (194).

6,14-Endoethenotetrahydrothebaine (196), the C-? unsubstituted pa-,rent, can be prepared by Huang MinIon reduction of the 7-oxo bridged'thebaine derivative (191) (196). 6,14-Endoetheno ketone (191) itself is

191

inactive as an analgesic at 100 mg/kg, but its 6,14-endoethano ketone(192) is half as potent as morphine. The two N-methyl substituted7-oxotetrahydrooripavine derivatives 193 and 194 are about two and fourtimes more potent than morphine, respectively (Table 3-18). The N-cyclopropylmethyl thebaine analog (195) is a mild antagonist, havingone-half the activity of pentazocine in the phenylbenzoquinone writhing

,III Diels-Alder Adducts of Thebaine III

Table 3.18

\Analgesic Activity of 7-0xotetrahydrothebaine and Oriparine

Derivatives

a Reference 196. bRats, ip.e

Relative to morphine = 1.0.d Antagonism relative to nalorphine = 1.0.,

CPM = cyciopropylmethyl.

assay. The thebaine base (196) is equipotent with morphine, whileconversion to the oripavine base (197) results in an increase in analgesicpotency of 30-40 times (196). Reduction of the double bond in eithercompound results in little change in analgesic potency compared to theunsaturated bases.

The increase due to O-demethylation at C-3 occurs as a generalphenomenon, increasing analgesic potency approximately 10-50 times, asevidenced also by the eightfold increase in rat tail pressure test activity (sc)for ethyl ester (199) compared to morphine (195). Demethylation of C-6also increases analgesic potency. Whereas the 6-methoxy ethyl ester (170)is inactive, the 6-hydroxy analog (198) is equipotent with codeine in the rattail pressure test. lncreasing the C-7 ester alkyl chain length in the3,6-dihydroxy compounds increases potency, with the butyl ester (200)being 40 times more potent than morphine (195).

In addition to thebaine, other structurally related alkaloids (197-199)react with methyl vinyl ketone, giving only a single isomer, the 7a-acylproduct. 6-Demethoxythebaine (201) and ,B-dihydrothebaine (202) formanalogous Diels-Alder addition products. ,B-Dihydrothebaine does not,however, give the conventional Diels-Alder adduct products when reactedwith acetylenic dienophiles (200).


201 202

2. Base-Catalyzed Rearrangements Diels-Alder adducts containing aC-7 ketone, such as thevinone (166), suffer base-catalyzed rearrangement(189,201) (Scheme 3-30, R = COCH3), initiated by enolization of theketone toward C-7. Both tex and 7{3Diels-Alder isomers yield the samerearrangement products, since, under reversible conditions, removal of theC-7 proton to form the enolate makes C-7 no longer asymmetric. C-7carbanion attack on the 4,5-oxygen bridge, with the formation of aC-7-C-5 carbon-carbon bond, produces a phenoxide anion at C-4 (204),which is either stabilized by alkylation (206) or attacks C-6 (205). Althoughthe three isomeric bases (203, 204, 205) are in equilibrium in methanolicpotassium hydroxide, base 205 is favored due to relief of strain arising fromthe 4,5-oxygen bridge and is therefore the rearranged base obtained inexcellent yield. Methoxide attack on 204 at C-6, C-17, or C-19, which is thecarbonyl of the C-7 substituent, is also possible in the methanol solvent.The two primary base-catalyzed rearrangement products of thevinone(207, 208) can be hydrolyzed with acid under mild conditions to yield anex,{3~unsaturated diketone, 18-acetyl-5,14-endoethanothebainone (209).

Dlels-Alder adducts containing a C-7 ester or nitrile (Scheme 3-30,R = C02CH2CH3, CN) are also rearranged by base, but the products donot usually proceed beyond bases 210 or 211 due to the decreasedelectron-accepting power of the C-7 ester or nitrile group compared to thatof the C-7 ketone. Such groups are ineffective in producing the equivalentof 205 (201,202). Further hydrolysis by acids yields the ex,{3-unsaturatedketones 212 and 213, which are analogous to structure 209.

.The Diels-Alder ketone nepenthone (168) readily forms the novel

Isonepenthone (214) (201,203) when refluxed in 5% methanolic sodiumhydroxide. This formation was quite surprising when first observed, but therearrangement product is stable due to relief of steric strain and minimiza-tion of nonbonded interactions. Mild acid hydrolysis of isonepenthoneinitially yields the C-18 {3-epimer, which equilibrates to pseudonepenthone(215).

An unusual base-catalyzed rearrangement (Scheme 3-31) is that of thedihydrothebainequinone (216) (204), which gives the phenolic diketone

III Diels-Alder Adducts of Thebaine 113

II\

a----'>: 7

R

203

166 R = COCH3

170 R = C02Et

174 R = CN

168 R = COC6HS )205

207 R = COCH3

~21. R' COC,',

R

2061R = H, CH3

209 R = COCH3212 R = C02Et213 R = CN

215 R = COC611S

Scheme 3-30. Base-catalyzed rearrangement products of ketones. esters, and nitriles.Reagents: (a) potassium hydroxide; (b) alkyl halide; (c) acid hydrolysis.

208

210

211

1R = H, CH3

R = COCH3

R = C02Et

R = CN

(217) (205). This product is sensitive to air oxidation and thus produces theisolatable dihydroflavothebaone enol methyl ether (218), the reaction beingdriven by aromatization of the cyc1ohexanedione ring. Hydrolysis yields anew alkaloid base (219), the 6,14-bridge saturated analog of the base-catalyzed rearrangement product of thebainehydroquinone (206), whichthen autoxidizes in alkaline solution to flavothebaone (220).

Much interesting chemistry has evolved from investigation of thebase-catalyzed rearrangement products of Diels-Alder ketones, ester andnitriles. Unfortunately, the few compounds that have been tested foranalgesic activity have been inactive. The dihydrothebainequinone adduct(216) has only one-tenth to one-fifth the potency of morphine in the rat tailpressure test by sc administration (204).

R1 R

222 H CH3

223 CH3 CH3

224 H CH2CH3

225 CH3 CH2CH3


b-..

216 217 218

e~

220(flavothebaone) 219 R - CH- 3

Scheme 3-31. Novel base-catalyzed rearrangement of dihydrothebainequinone.

Reagents: a, potassium hydroxide; b, airoxidationor potassium hydroxide; c, methyl

sulfate; d, hydrolysis; e, alkali.

3. Alkyl, Carboxyl, and AminoDerivatives Many derivatives of 6,14-

endoethenotetrahydrothebaine have been obtained from the 7a-ketone,-ester, and -nitrile adducts, which have repeatedly proved to be favorablestarting materials. Huang Minion reduction of the 7-acyl products hasprovided 7a-alkyl oripavines, whereby demethylation of the phenolicether has also occurred (207). Thus, the Diels-Alder adduct aldehyde(221) and methyl ketone (166) yield 7a-methyloripavine (222) and7a-ethyloripavine (224) respectively (Scheme 3-32), both of which canbe methylated to the corresponding thebaine analogs 223 and 225, allof which can be converted to N-substituted 7a-alkyl derivatives viaeither the nor-compounds or the N-acyl intermediates. A 7-methylene pro-duct (227) has been obtained by Hofmann methylation of the 7-dimethylaminomethylene derivative (226), obtained from the ethyl acry-late adduct (221) via the 7-dimethylamino amide intermediate. The7-ethylidene compound (228) has resulted from the p-toluenesulfonateof the C-19 secondary alcohol of 166.

III Diels-Alder Adducts of Thebaine

a~

R'

221

166

H

115

Scheme 3-32. Synthesis of 7-alkyl derivatives. Reagent: (a) Huang Minion.

R

226 CH2N(CH3)2

227 = CH2

228 = CH-CH3

The 7a-methyl and -ethyl oripavines 222 and 224 are equipotent withand three times less potent than morphine, respectively, in the rat tailpressure test by sc administration, whereas the methylene and ethylidenethebaines 227 and 228 have little or no activity (196). A tetrahedral carbonat C-7 therefore seems to be associated with higher activity than a trigonalcenter.

The ethyl acrylate adducts of thebaine have been used as startingmaterials for the incorporation of peptide segments derived from theendogenous opiate ligand leucine-enkephalin (229), in essence resulting in

---COR'

170 R' OEt

R R'

232 CH3 Leu-OEt233 CH3 Phe-Leu-OEt -

C02R'234 CH3 Gly-Phe-Leu-OEt

235 H Leu-OEt


the union of the rigid morphine ring system of the "Bentley adducts" withthe lipophilic portion of the enkephalins (208). The rationale rests on theobservations of common core elements of leucine-enkephalin comparedto morphine skeletons: (a) the tyrosine moiety, in which the tyrosineresidue in the natural ligand, in contrast to morphine, is flexible enough toadopt various conformations, and (b) the "tail" of the enkephalins,corresponding to the C-19R alcohol portion of known very potent analge-sics, such as etorphine.

Thus, the major isomer 7a-ethyl thevinoate (170) has been hydrolyzedwith base to the thevinoic acid (230) and then converted to the acidchloride (231) by reacting with oxalyl chloride before coupling withL-Ieucine, L-phenylalanyl-L-leucine, and glycyJ-phenylalanyl-L-leucineethyl esters to yield thebaines 232, 233, and 234, respectively (Scheme3-33), which can all be demethylated to give tthe corresponding 3,6-dihydroxy derivatives using hydrogen bromide in glacial acetic acid. Forthe L-phenylalanyl-L-Ieucine analogs, the C-terminal ester of the peptidehas been subsequently reduced to the primary alcohol using sodiumborohydride. The leucine-enkephalin dihydroxy analog (235) is a potent

230 R' OHa,b-- 231 R' C1

J

1

Scheme 3-33. Synthesis of peptide morphine derivatives. Reagents: (a) sodium hydrox-ide; (b) oxalyl chloride.


GlY-Gly-Phe-Leu

HO

229

Etorphine Leucine-Enkephalin

(Tyr-Gly-Gly-Phe-Leu)

analgesic in the mouse hot plate assay (sc), displaces etorphine in theopiate receptor binding assay, and has an overall pharmacological profilesimilar to that of morphine.

Opiate receptor probes have been synthesized by alkylation of a7a-amino oripavine adduct (236) (Scheme 3-34), this Diels-Alder adductbeing conveniently obtained from the 7a-acetyl phenol of thevinone (166)via a 7a-acetamide intermediate obtained by the Schmidt reaction (209).Thus, 236 has been converted to the isothio-, cyanato-, bromoacetamido-,and methylfumaramido-derivatives; each alkylating agent has then beenassayed for po and 8 receptor selectivity (210). Only 7a-methylfumaramido6,14-endoethenooripavine (FAO, 237) has proved to be a highly selectivealkylator of 8 receptors with no cross-reactivity for po receptors.

An alternative synthesis of 7a-amino compounds has involved Curtiusdegradation of the 7a-ethyl ester (170) via the hydrazide and azide to givethe benzyl urethane (238), which yields 236 on hydrolysis (209).

The 7a-ethyl ester (170), by way of the acid chloride (231), ontreatment with primary or secondary amines yields 7a-amides (239) (211)(Scheme 3-35), including the 7a-acetamido base (240), although some ofthese are also available by direct Diels-Alder addition of acrylamidedienophiIes to thebaine (212). Reduction with lithium aluminum hydrideyields 7-a-aminomethyl compounds (241); reduction of the primary amide(240) yields the methylamine (242) only when a large excess of reducingagent is used (211). The 7,B-methylamino, 7a-methyl compound, how-ev~r, can also be obtained directly from the 7,B-cyano, 7a-methyl adduct byreduction with lithium aluminum hydride (213). Derivatives with a ni-trogen substituent other than methyl and the oripavine bases have also been

'prepared. The 7a-amido and 7a-aminomethyl derivatives in each N-substituted series all have analgesic activity less than that of the corres-ponding secondary alcohols. None of the intermediates has any significantanalgesic activity. The effect of C-3 O-demethylation generally accountsfor a 5- to lO-fold increase in analgesic activity, as has been observed inother series of the morphine-codeine group.

243 R CH) 70',80'

244 R CH) 7{3,80'

245 R phenyl 70',80'

246 R phenyl 7{3,8a


166

IINHR'-236 237

OCH3t

R' = COCH=CHC02CH3

(FAO)

238

i c,d

170

Scheme 3-34. Synthesis of an FAa opiate receptor probe. Reagents: (a) sodium azide,perchloric acid (Schmidt); (b) hydrolysis; (c) hydrazine; (d) sodium nitrite, acid; benzylalcohol.

4. 7,8-Disubstituted Adducts In addition to monosubstituted and 1,1-disubstituted (178) ethylenes, cis 1,2-disubstituted (179) ethylenes addreadily to thebaine. Trans 1,2-disubstituted ethylenes, both symmetricaland unsymmetrical, containing bulky groups (179), have been usedsuccessfully as dienophiles. For cis and trans diacetylethylene (R1 = R2 =COCH3, Scheme 3-27) and dibenzoylethylene (Rt = R2 = COC6Hs), theexclusive isolated product bases have been characterized spectroscopicallyas the 7a, 8a (243, 245) and 7{3, 8a (244, 246) diester compounds. The


231HNR'R"~

"

,CONR

'R"

239

240 R' R" H

/R' = R" H, alkyl,

aryl

242 R'

Scheme3-35.num anhydride.

241

= R" = H

Synthesis of7a-amido and methylamino derivatives. Reagent: lithium alumi-

H (COR)

COR (H)'~,~

""'COR (H)

'H (COR)

- CH3

COR'

~255 R' R" C6H5

256 R' C6H5

R" OCH3

~257 R' R" C6H5

258 R' C6H5

R" OCH3

- CH3

120

247

CH3

~I

,CH3

o .~ ~"'''CH3

RO '.

OCH3250 R = CH3

251 R = H

3 Synthesis of Morphine, Codeine. and Related Alkaloids

254

1c,d

d'252

Scheme 3-36. 7.8-Disubstituted adducts. Reagents: (a) hydrochloric or phosphoric acid,ethanol; (b) lithium aluminum hydride; (c) p-toluene sulfonyl chloride; (d) potassiumt-butoxide, butanol; (e) hydroxide; (f) acid hydrolysis.

more stable stereoisomeric products result from the preference of bulkysubstituents for the a-configuration at C-S due to the proximity of thenitrogen-containing ring. No isomeric 7a,S{3 and 7{3,S{3adduct bases areformed.

Entrance to 7,S-disubstituted adducts (214) can be achieved eitherdirectly by reaction with trans or cis 1,2-disubstituted dienophiles (179)(Scheme 3-27) or by conversion of the maleic anhydride adduct (247) tothe diester (248) (204), which can then be reduced with lithium aluminumhydride to the diol (249) (Scheme 3-36). This diol serves as a useful startingmaterial for the generation of additional 7,S-disubstituted adducts, for


COR'

259 R' R" = C6H5

C6H5,

OCH3

260 R'

R"

COR'

Scheme 3-37. Base-catalyzed rearrangement of 7,8-disubstituted adducts. Reagents: (a)hydroxide; (b) acid hydrolysis.

example, by conversion to the ditosylate, followed either b7 hydrogen~ly-sis with lithium aluminum hydride to give the 7a, Sa dimethyl codlde(250) or by reaction with potassium (-butoxide in (-butyl alcohol to yieldthe diene (252). Diester (248) is unstable toward base and is rearranged ina manner similar to that of the C-7 monoester (170), giving the vicinal transdiester (253) which can be hydrolyzed with dilute acid to the phenolic transdisubstituted a,{3-unsaturated ketone (254).

When the 7-substituent is a phenyl ketone (Scheme 3-37), both cis andtrans orientations of the C-7, C-S substituents in the compound pairs 255,

R Rl

261 CH3 CH3

262 H CH3

263 CH3 Allyl

264 CH3 CPM


257 and 256, 258 yield the same base-catalyzed rearrangement hemiketaldicarbonyl intermediate due to C-7 epimerization. On acid hydrolysis, thediketones in each case afford a phenolic trans disubstituted a,{3-unsaturated ketone: 255, 257 yielding 259 and 256, 258 yielding 260.

The dialkyl compounds show improvement in analgesic activity com-pared to the monoalkyls. The 7a,8a-dimethyl base (250) is 18 times morepotent than morphine; its oripavine analog (251) has 200 times the potencyof morphine (213) in the rat tail pressure test (sc). But the tetahydrofuranbase (261) has only 0.9 times morphine's analgesic potency. Conversion to

265

the oripavine (262) results in 12 times morphine's potency; its N-allyl andN-cycIopropylmethyl codides (3-methoxy) (263, 264) are weak morphineantagonists. Interestingly, the N-cycIopropylmethyl phenylpyrrolidinocompound (265) is a weak analgesic. In general, any unsaturated substitu-tion at C-8a results in a decrease in or loss of analgesic activity, however, asimple alkyl group increases analgesic potency.

III Diels-Alder Adducts of Thebaine ]23

Thebainea

'"

b266

267 R' = Me, Et 268 R' = Me, EtScheme3-38. Adducts formed from acetylenic dienophiles. Reagents: (a) dimethyl

acetylencdicarboxylate; (b) methyl or ethyl propriolate.

Reaction of thebaine with acetylenic dienophiles (215, 216) (Scheme3-38) such as dimethyl acetylenedicarboxylate yields an unsaturated 7,8-disubstituted analog, compound 266. Reaction with methyl or ethylpropiolate yields the 7-monosubstituted products 267. Since both productsare thermally unstable, however, reaction usually gives rise to rearrange-ment benzazocine isomers. Work with propiolic esters has demonstratedthat reaction of thebaine with acetylenic dienophiles is solvent dependent(200), with new types of adducts (268) being isolated in polar solvents (216,217); these abnormal products result from C(9)-N bond scission. Addition-al work has been done on the irradiation products of 266 (218) and its6,14-endoethano derivatives.

1Z4 3 Synthesis of Morphine. Codeine. and Related Alkaloids

Fig. 3-/.

5. Stereochemical Assignmellls Stereochemical assignment of the C-7and C-8 epimers of thebaine and oripavine bases formed by Diels-Alderaddition of electrophilic olefins and subsequent transformation has reliedheavily on proton NMR, including homonuclear field-sweep spin-decoupling and nuclear Overhauser effect (NO E) techniques. In additionto elucidation of the absolute configuration of the asymmetric centersgenerated by these additions, NMR and supportive infrared (IR) andultraviolet (UV) spectroscopy have elucidated the alkaloid base skeletonand stereochemistry of base-catalyzed rearrangement products.

In summary, the NMR findings indicate the following for virtually allDiels-Alder adducts studied (219) (Fig. 3-1):

1. The chemical shift for H-513 is diagnostic for C-7 configurationassignment, the range for the average chemical shift being, with fewexceptions, 4.57:t 0.05 ppm for a 7Ci substituent and 5.07:t 0.12ppm for a 713substituent. This downfield shift in 713compared to 7Cicompounds also holds for all analogs produced by modifications ofthe initially formed adducts.

2. H-513 and H-713 are coupled to H-18 in the 7Ci-compounds, whereinthe three protons and the intervening carbon atoms approximate aplane in which the connecting bonds resemble a W.

3. The C-8 geminal protons show unique and characteristic variations inchemical shift, influenced by the C-17-C-18 double bond as well as bythe nature and stereochemical orientation of the C-7 substituent.

4. H-813 and H-8Ci show a large difference in chemical shift based onthe difference in the shielding effect of the tertiary nitrogen atom(electron pair) held in proximity to H-813 by the rigid ring system.H-813 appears downfield from H-8Ci, whose average chemical shiftis, with few exceptions, for either a 7Cior a 713substituent, 1.35 :t0.15 ppm.

III Diets-Alder Adducts of Thebaine 1Z5

5. H-813 can be assigned on the basis of spin decoupling experimentssince H-813 is coupled to H-7Ci and H-8Ci, whose chemical shift isknown.

6. Very small long-range coupling exists between H-813 and H-17, thestereochemical environment being similar to that between H-713andC-18.

This NMR documentation, including the experimentally observed spinsystems, coupling constants, and anisotropic tertiary nitrogen effect on theC-8 protons, confirms that the Diels-Alder adducts of thebaine are not C-8but C-7 derivatives, having an "endo" and not an "exo" disposition of the6,14-etheno bridge and being "inside" the tetrahydrothebaine ring system.

The C-5 proton in the reduced C-19 tertiary carbinol derivatives of theethyl acrylate product (170) has proved characteristic when compared tothe C-5 proton in the methyl vinyl ketone adduct (166) (189): 4.60 ppm(7Ci-) and 5.17 (713-) for the monosubstituted ethyl esters versus 4.55 ppm(7Ci-) and 4.98 (713) for the methyl ketones.

Chemical shifts of the methyl and methylene protons of the ethoxy.group, in addition to the C-5 proton, have characterized ethyl ester adducts'resulting from 1,1-disubstituted dienophiles (178). In the adducts studied(171,172, 173) and compared to the 7,7-bisethoxycarbonyl derivative, thethree ethoxy signals absorb at lower fields when the ethoxycarbonylgroup is in the l3-configuration. For example, the ethyl 2-acetoxyacrylatedienophile produces a 7Ci-carboxy ethyl ester product (173) that has NMRsignals at 4.17 ppm (-CH2), 1.21 (-CH3), and 5.45 (5-H), whereas the713-epimer has 4.32-, 1.32-, and 4.71-ppm shifts, respectively.

Both the H-513resonance and the NOE between the 7Ci-methyl and 8Ci-Hand 813-H have characterized the 7Ci-methyl-713-cyano-thebaine adduct(175) (178).

In 7,8-disubstituted compounds (244, 246), the coupling constant (6 H~)for H-713 and H-8o: corresponds to a transoid vicinal arrangement that ISdistinguishable from the cisoid (11 Hz) (179). In addition, H-5 haslong-range coupling with H-8, showing H-5 to be 13. The low fieldresonance of H-8 is diagnostic for 13stereochemistry, based on the effect ofthe the nitrogen lone pair. Increasing or decreasing the electron density atnitrogen, that is, preparation of N-oxides or addition of acid, withconcomitant measurement of the absorption of the H-8 resonance, allowsconfirmation of the 813-H assignment.

For rearrangement products such as 253, the olefinic bridge signals forH-8 (doublet, 5.83 ppm; J8.7 = 9 Hz) and H-7 (doublet of doublets,5.08 ppm; J7.8 = 9, J7.5 = 2 Hz) characterize and differentiate the etherfrom a phenolic product formed from ether ring opening (214).


The sulfonyl adducts 177 and 178 have been assigned as 7a on the basisof the difference in the resonance of the CoSH proton when compared tothe generated 7{3-epimers (190). The 7{3-sulfonyl group also produces aneffect on CoSH that is quantitatively similar to that observed with other7{3-electron attracting groups.

In cases where structural assignment of stereochemistry has not beenpossible by proton NMR spectroscopy, derivatization has proved useful.For the l,l-disubstituted ethylene, 2-chloroacrylonitrile, the epimericad ducts (176) had to be converted to spiroaziridines 269 and 270 byreduction with lithium aluminum hydride (178). Knowing that cyclization

269 R' H 270 R' H

271 R' P-C1C6H4CO 272 R' P-C1C6H4CO

is stereospecific and proceeds with inversion of configuration allowed (a)interpretation of proton NMR data for these spiroaziridines and the twop-chlorobenzoyl derivates 271 and 272, and (b) assignment of stereo-chemistry at C-7 in the original thebaine adducts, the most abundant beingthe 7{3-cyano-7a-chloro isomer and producing 269.

The aziridines have only slight agonist activity in the rat tail pressuretest; their p-chlorobenzoyl derivatives (271, 272), however, are three andseven times more potent than morphine, respectively, as analgesics in therat tail pressure test (sc) (178).

B. Functionalization at C-19: Alcohols

Although the adduct of thebaine and methyl vinyl ketone, thevinone(166), is rearranged in base via the C-7 carbanion under reversible enoliza-tion, the initial enolization of the ketone takes kinetic control, so thatvaluable products of reaction at the terminal carbon are possible. Oneuseful sequence (Scheme 3-39) involves treatment of 166 with trimethylorthoformate and perchloric acid in methanol to yield dimethyl ketal (273),followed by thermal elimination of methanol to yield an enol ether, both of

(JlNH2

278 O~R, R = alkyl

Scheme 3.39. Reactions of thevinone at the terminal carbon atom. Reagents: (a) trimethyl

orthoformate, perchloric acid; (b) heat; (c) phosgene, dimethylformamide.

III Diets-Alder Adducts of Thebaine

166

273

-R

127

y

CH3 _

f: ~ CHOCH 0 ~3

I 274

275 R = tJ where X = 0

276 where X = NR'; R' = H, alkyl,aryl

277 R =

which form the methoxy enal (274) by reaction with the Vilsmeier reagentformed from phosgene and dimethylformamide. This enol ether of {3-ketoaldehyde condenses readily with a variety of active methylene com-pounds and reacts with alkyllithiums to form 7a-substituted heterocycliccompounds (220), for example, the bases (275-277) and the a,{3-unsaturated ketones (278), which can be reduced to saturated ketones. Thedimethyl ketal (273) is the key for the synthesis of 3-hydroxy andN-substituted 7a-ketone and 7a-ester substituted bases. All of thesecompounds prove to be difficult to make by other conventional routes.

R'a or : ~R"~IIC

b or c \OH

OCH)

(A)

R' R' R"

166 CH) 279 H CH)

169 OCH) 280 CH3 H

170 OCH2CH) 281 CH3 CH3


282 R' = R" = CH3Scheme ]-40. Synthesis of C-19 alcohols of 6, 14-endocthenotetrahydrothebaine. Re-

agents: (a) grignard reagent or lithium alkyl; (b) sodium borohydride; (c) aluminum isopro-poxide.

1. Thevinols and Orvinols To further study modifications of the7-keto group involving removal of electron density at this position,secondary and tertiary alcohols have been readily prepared from 70'.-aldehydes and 7O'.-ketones by reaction with aluminum I alkoxides, sodiumborohydride, lithium alkyls, and grignard reagents. For example, reduc-tion of thevinone (166) with aluminium isopropoxide yields the secondaryalcohol 279 almost exclusively, although switching to sodium borohydrideproduces a 50:50 mixture of the two C-19 diastereoisomeric alcohols 279and 280 (Scheme 3-40). Treatment of thevinone (166) with methyl grignardprovides a small amount of opened compound (282) along with thedimethyl carbinol (281) (221), which is also obtainable from 7O'.-esters(169) or ethyl thevinoate (170). Generally, the C-19 alcohols can be easilyprepared by reaction of grignard reagents or lithium alkyls on themonosubstituted C-7 aldehydes, ketones, or esters (175), the stereochem-istry at C-7 in the starting material being the determinant of the C-19


configuration of the product. When no competitive processes are opera-tive, the grignard reaction is highly stereoselective, giving a high yield ofone pure diastereoisomer of the tertiary alcohol, whereas reactionwith lithium alkyls shows less stereoselectivity and produces more sideproducts.

Reactions of ketones with grignard reagents R"MgX, however, can becomplex, leading to the following types of products (221).

1. Tertiary alcohol (A), the normal and the major grignard reactionproduct

2. Tertiary alcohol diastereoisomeric with (A), also a normal but aminor reaction product

3. Secondary alcohol ((A), where R" = H), the major grignard reduc-tion product formed when R" contains a l3-hydrogen (borohydridereduction product)

4. Secondary alcohol diastereoisomeric with (A), R" = H, a minorreduction product (Meerwein-Pondorff reduction product)

5. C-4 phenol, from base-catalyzed rearrangement of the ketone fol-lowed by grignard, reaction at the carbonyl group

The grignard reduction process is also. highly stereoselective, usuallyproducing almost exclusively one isomer, although a minor amount of thediastereomer can be isolated. In some cases, this reduction processseriously competes with the normal grignard reaction, such as in the6,14-endoethano bases, where 40% of the product is the reduced com-pound.

The most extensively studied series of alcohols is that derived fromthevinone (166), which is as potent an analgesic as morphine. Bothgrignard reaction with and grignard reduction of this ketone lead toproducts of the same stereochemical series (A), compounds 280 and 281.However, the Meerwein-Pondorff reduction produces products that haveopposite configuration at C-19, compound 279, resulting from free rotationabout the C-7-C-19 single bond and preferential hydrogen transfer to the"top side" of the carbonyl group in the aluminium coordinated complex ofthe transition state. Reaction of thevinone with n-propyl or isobutylmagne-sium halides also results in diastereomer (280).

The series of secondary and tertiary alcohols of the N-methyl thebaineseries illustrates the higher analgesic activities found in the tertiaryderivatives compared to the secondary bases 279, 280, 286, and 295 inseries A (alkyl derivatives) and 298 and 300 in series B (aryl derivatives)(Table 3-19). The effect of increasing alkyl chain length in a homologousseries is shown most dramatically in series B, where a one-methylene unitincrease from phenyl in 299 to benzyl in 301 results in a 2000-fold increase

CH3

Analgesia,"R' R" Tail Pressure Testb

279 H CH3 (Series A) 1<280 CH3 H 0.09281 CH3 CH3 2.7283 CH3 CH2CH3 20284 CH3 (CH2hCH3 96285 CH3 CH2(CH3h 10286 H CHiCH3h 5.3287 CH3 (CH2hCH3 24288 CH3 CH2CH2(CH3h 2.5289 CH3 CCCH3h 0.1290 CH3 (CH2)4CH3 IS291 CH3 (CH2hCCH3h 30292 CH3 (CH2hCH3 2293 CH3 (CHzhCH3 0.03294 CH3 eyclopentyl 1.0295 H cyclohexyl 9.0296 CH3 cyclohexy 1 59297 C6HS CH3 (Series B) 0.09298 H C6HS 0.01299 CH3 C6Hs 0.07300 H CH2C6Hs 7.6301 CH3 CH2C6Hs 150302d CH3 (CH2hCt;HS 500303 CH3 (CH2hC6Hs 2.1

a Reference 221. bRats, SC.< Relative to morphine = 1.0. d Phenethyl thebaine (PET).

130 3 Synthesis of Morphine, Codeine, and Related Alkaloids III Diels-Alder Adducts of Thebaine

Table 3-19

Analgesic Activity of C-19 Alcohols of

6,14- Endoethanotetrahyd rothebaine (Thevinols)

Table 3-20

131

Analgesic Activity of Thevinols with Similar Substitution at C-19

R' R"Analgesia:

Tail Pressure Test b

304305306

307308309

310311312

HCH2CH3(CHzhCH3C6Hs(CHzhCH3C6HSCH2CH3C6HSC6Hs

CH2CH3CH2CH3(CHzhCH3

(CHzhCH3(CHzhCH3CyclohexylC6HSC6HS

CH2C6Hs

O.S<2.53.10.23.00.04

oo

u Reference 221. bRats, sc.< Relative to morphine = 1.0.

Only compounds with a hydrogen or methyl group as one substituent of thealcohol display significant activity. The preferred substituent for R' ismethyl. For a given R" increasing the size of R' beyond methyl decreasesthe analgesic potency (Table 3-20). The alcohol 283 is 30 times morepotent than its diastereomer, the R-configuration at C-19 usually being themore active of a diastereomeric pair.

In these tetrahydrothebaine alcohols, further modifications have beenmade in an attempt to increase potency. Esterification of the C-19 hydroxylgroup in the secondary alcohols 279 and 280 has not affected the analgesicpotency significantly; esterification of the C-19 tertiary alcohols hasgenerally been unsuccessful, as well as a-alkylation (221).

Demethylation at C-3 in codeine derivatives to yield morphine deriva-tives has been well documented to result in increased analgesic potency.Demethylation at C-6 in other opiate alkaloid derivatives results in asignificant decrease in potency. Therefore, C-3 hydroxyl and C-6 methoxylare the preferred substituents for maximizing activity. The 6,14-endoetheno and 6,14-endoethano C-19 alcohols have been selectivelya-de methylated at C-3 to oripavine derivatives by heating with potassiumhydroxide in refluxing diethylene glycol, since reaction with acidic reagents

in potency; an additional unit increase (302) leads to a further 3-foldincrease and then to a sharp 250-fold decrease (303). For alkyl substituentsof series A, a peaking effect in potency occurs at a 3- to 5-carbon chain(284, 287, 290). Branching effects in R" vary, usually, however, decreasingin potency relative to the straight chain counterparts (285, 288, 289). In thethebaine N-methyl series, compound 302 is the most potent analgesic.


Table 3-21

Analgesic Activity of C-3 Substituted Thevinols

- CH3

II'C_R'\OH

OCH3

RAnalgesia,"

Tail Pressure TestbR'

281313314283315284316J

317287318291319320

CH3HCaCH3CH3HCH3HCaCH3CH3HCH3HCaCH3

CH3CH3CH3CH2CH3CH2CH3(CH2hCH3(CH2hCH3(CH2hCH3(CH2hCH3(CH2hCH3(CH2hCCH3h(CH2hCCH3h(CH2hCCH3h

2.7e

635520

33096

32008700

245200

3092001300

.Reference 222. bRats, sc.e Relative to morphine = I. d Etorphine.

leads to acid-catalyzed rearrangement products (222). The 4,5-oxygenbridge, a phenolic ether, is unaffected under these conditions. Esterificatonof the C-3 phenolic hydroxyl group of several 6,14-ethenotetrahydro-oripavines has been easily achieved by conventional methodology. Asubstantially more potent series of analgesics has resulted from thedemethylation at C-3; esterification only marginally improves the potencyover that of the phenols.

The alcohols of the grignard reaction product with thevinone (166)illustrate the importance of the C-3 hydroxyl and C-3 acetate in substantiallyincreasing analgesic potency several hundredfold (Table 3-21). The effectis very pronounced when the two alkyl groups on C-19 are methyl andn-propyl (compound 284, the most active analog in series A of Table 3-19).The oripavine (316) is more than 300 times as active as the thebaine base,while the acetate (317) is about 900 times as active as 284, over two times asactive as 316. Usually, however, acetylation, while still retaining more


activity than morphine, causes reduction in activity compared to theoripavine bases, as in compound 320.

One unique derivative of etorphine (316) that has a benzoylthio groupreplacing the phenolic hydroxyl at C-3 has been used to test the effect ofoxygen-sulfur interconversion on analgesic activity (223). S-etorphine(321), synthesized via a Newman-Kwart rearrangement of a thiocarba-mate intermediate, has two (oral) and three (sc) times the potency of .

morphine in mice. This sulfur derivative, however, has very low JJ-opioidreceptor affinity, as measured by the inhibition of tritiated naloxone.Etorphine itself has a ~ receptor affinity 20 times that of morphine,whereas S-etorphine has only 1/40th the affinity of morphine, slightly morethan 1/800th that of etorphine.

fH3

,,'c -(CHZ) ZCH3

\H

OCH3

321S-etorphine

Etorphine (Immobilon) (316) [and its C-3 acetate (317), which hasalmost 9000 times the analgesic potency of morphine] has been extensivelystudied both in vitro and in vivo (224) and has found widespread use as ananalgesic agent to immobilize large wild game animals due to its consider-able margin of safety. The diastereomer of etorphine shows a potencydropoff of 50-fold, so that, as usual, the C-19R alcohol is the more potent.Etorphine is 1000-80,000 times more potent than morphine when adminis-tered sc, depending on the test protocol and the animal species used (255a).It is absorbed sublingually in dogs; sublingually in humans, a 0.5- to1.5-~/kg dose is equivalent to 5-10 mg morphine given im or by ivinjection (225b). The undesirable side effects are similar to those ofmorphine; however etorphine depresses the CNS to a greater extent thanmorphine does.

Interestingly, studies on tritiated etorphine cerebral receptor binding invivo in rats (224a) have demonstrated an extremely low fractional receptoroccupancy at analgesic doses (2% at the EDso, tail flick assay). In rats, thisanalgesia is rapidly reversed, the in vivo dissociation half-life being about50 seconds. Results support a receptor binding-effect model based on lowfractional receptor occupancy at analgesic doses of a pure agonist such asetorphine.

Analgesia:X R R' Tail Pressure Testb

281 CzHz CH3 CH3 2.7e322 ~H4 CH3 CH3 2.9287 ~Hz CH3 (CHzhCH3 24323 ~H4 CH3 (CHzhCH3 240324 ~H4 H (CHzhCHJ 12,000291 ~Hz CH3 (CHzh(CHJ)z 30325 ~H4 CH3 (CHzh(CH3h 150326 ~H4 H (CHzh(CH3h II ,000299 ~Hz CH3 C6Hs 0.07327 ~H4 CHJ C6Hs 0301 ~Hz CH3 CH2C6Hs 150328 ~H4 CH3 CH2C6Hs 110

a References 221,222. bRats, sc. e Relative to morphine = I.

R H, CH3

X C2H2, C2H4

R'

= R"Y C-"

\OH


Table 3-22

Analgesic Activity of 6, 14-Endoetheno- versus

6.14-Endoethanotetrahydrothebaine C-19 Alcohols

- CH3

II I ICR

I

"- OH

The N-methyl 3-deoxy compounds of various 6,14-endoetheno tertiaryalcohols have been prepared; generally, these are more potent analgesicsthan the thebaine analogs but less potent than the oripavine derivatives(226).

Catalytic reduction of the 6,14-endoetheno tertiary alcohols to the6,14-endoethanotetrahydrothebaines has been accomplished only at ele-vated temperature and pressure with Raney nickel (227), although theseproducts can also be formed in reverse sequence by (a) reduction of the6,14-endoetheno ketone to the ethano ketone and (b) subsequent trans-formation of the ketone to C-19 alcohol. Grignard reaction of the6,14-ethano ketone follows the same general patlerns as the 6,14-ethenoanalogs with the same stereospecificity (221). Reduction of the 6, 14-ethenobridge usually increases the activity of codides relative to that of theirunsaturated analogs, such as the lO-fold increase seen in 323 compared to287 and the S-fold increase seen in 325 compared to unsaturated analog 291(Table 3-22). While this holds for alkyl substituents at C-19, it does not


a:>

"y

329

( c or

d,eI'Y

331 330R1 = alkyl, alkenyl,

alkynyl

Scheme 3-41. Synthesis of nor-thebaine and oripavine derivatives. Re~gents:. (a)

cyanogen bromide, heat; (b) potassium hydroxide, diethylene glycol; (c) appropnate halIde;(d) appropriate acyl halide; (e) lithium aluminum hydride.

hold well for aryl substituents in the codide series, such as compounds 3~7and 328. Reduction in the morphides yields tremendous increases manalgesic activity. The 6,14-endoethano phenols 324 and 326 have 12,000and 11,000 times the potency of morphine, respectively (222).

2. Nor-thebaine and -oripavine Bases Many C-19 tertiary alcoholswith nitrogen substituents other than methyl have been made, many. ofthese tertiary amines being analogs of nalorphine. The secondary ammooripavine and thebaine bases (330) are intermediates, being produced fromthe N-methyl compounds via the N-cyano compound (329) or from a .N,N I-methylenebisnor adduct, produced by reaction with cyanogen bromideand ethyl or methyl azodicarboxylate, respectively (Sche~e 3-41) ~~22).The N-cyano compounds are then hydrolyzed under alkaline conditIOns,conditions also effecting O-dealkylation at C-3, to the nor compounds

R' R1 R Agonism Antagonism

332 CH3 CPM' CH3 OAJ

333 CH3 CPM H 35334 CH3 Allyl CH3 0.02'335 CH3 Allyl H 2.2336 CHzCH3 CPM CH3 0.2337 CHzCH3 CPM H 70

338 n-Propyl Allyl CH3 0.75339f n-Propyl Allyl H 20340 !sopentyl CPM CH3 3.8341 !sopentyl CPM H 48

a Reference 226. bRats, sc.,CPM = cyclopropylmethyl. ,

Relative to morphine = 1.0.d Relative to nalorphine = 1.0.f

Alletorphine.


(330), which are then alkylated, alkenylated, or alkynylated to N-substituted bases (331) by reflux with the desired halide or treatment withthe acyl halide followed by reduction of the amide with lithium aluminumhydride. In all cases, pure C-19 isomers of phenolic bases can be obtainedif pure starting alcohols are used. Heating the symmetrical or unsymmet-rical bisadduct intermediate with alkyl or acyl halides in the same manneralso produces stereochemically pure products; however, only reactive alkylhalides can be used and only methoxy (not phenolic) bases can beobtained. N-substituted compounds in both the 6,14-etheno and 6,14-ethano series are accessible by these routes.

Replacement of N-methyl by hydrogen and other groups has been donein most series of alcohols, in addition to 7a-ketones and -esters, resultingin varying agonist and antagonist effects (222). No particular group hasconferred morphine antagonist properties on all bases; however, groupssuch as n-propyl, allyl, and cycIopropylmethyl have given rise to thehighest proportion of narcotic antagonists. For example, the N-cycIopropylmethyl thebaine analogs of the 7a-methyl, 7a-ethyl, and7a-propyl ketones, as well as those of the 7a-methyl and 7a-ethyl esters,show narcotic antagonistic activity. The trends (191,228) shown by theseN-substituted bases (Tables 3-23, 3-24) are as follows:

1. Generally, oripavines have greater morphine antagonism than thecorresponding thebaines, so that there is less intrinsic agonist activity.For example, in the N-allyl series, a weakly analgesic thebaine,compound 334, gives a strong antagonism on demethylation at C-3 tothe oripavine base (335).

2. The size of the R' group and the C-19 configuration both influencethe intrinsic activity in the N-substituted 6,14-endoetheno bases.

3. In the N-methyl Diels-Alder adducts of thebaine (Table 3-19),increasing the size of the R" group when R' is methyl tends toincrease analgesic activity. In the C-19R series of allyl and CPMnorthebaine derivatives (Table 3-23), potency also increases withincreasing chain length when one C-19 substituent is methyl. Max-imum analgesic potency peaks at the R' = n-propyl, butyl range(compare 336 to 340, 334 to 338).

4. In the N-cycIopropylmethyl nororipavines, the change from methyl(333) to ethyl (337) increases antagonism, but a further increase inalkyl chain length to the propyl or isopentyl carbinol (341) conferspowerful agonism and no antagonism (Table 3-24). In the N-allylnororipavines, this change from antagonism to agonism also occursbetween methyl (335) and propyl (339). Both the N-CPM and N-allylethyl carbinols 337 and 344 are powerful antagonists in the rat tail


Table 3-23

Analgesic Activity of N-Substituted Thevinol Derivatives

N_R1

"CH 3II'C_R,

,OH

OCH3

Analgesia," Tail Pressureb

pressure test, but the analogous n-propyl carbinols 342 and 345,derivatives of etorphine, are agonists.

5. In the C-19S cycIopropylmethyl series, when R' is methyl, the amountof agonist character increases with increasing size of t?e othe~ al~ylsubstituent, with the change from antagonism to agoms~ begmnmgwith propyl or butyl. Here the transition is les~ dramatic: however,since the potency decreases with increasing ch~m length, m contrastto the diastereomeric series, where potency mcreases. .

6. While N-cycIopropylmethyl noretorphin.e (~42) has 100(019;)

11~es

morphine's analgesic potency, the opposite ~Iastereom~r IS amorphine antagonist equivalent to nalorphme (rat tall ~res~ure).However, 342 has 3!lOths the antagonist activity of nalorphme 10thetail flick assay.

Alletorphine (339) is 50-100 times more potent an analgesi~ th:nmorphine in rats (sc, rat tail pressure test), showmg much lower resplrato y

~H)--

'IIC ~R'IOH

CH)

Analgesia, a Tail Pressureb

R' R EDsn (mg/kg) ADso (mg/kg)

333 CH3 CPMc O.Ol3d337 CH2CH3 CPM 0.02342 (CH2hCH3 CPM 0.002'343 (CH2hCH] CPM 0.026335 CH3 Allyl 0.21344 CH2CH] Allyl 4.2345 (CH2hCH3 Allyl 0.033

R' R

346 Et CPM

347 n-propyl Allyl

348 isopentyl CPM


Table 3-24

Analgesic Activity of N-CPM and N-Allyl Orvinols

Q

Reference 228. bRats, sc or ip.CCPM = cyc1opropylmethyl. d Antagonism.,

EDso of morphine = -1.7 mg/kg.

depression than either morphine or etorphine and giving a low acutetox~city (229). T~is se~aration of effects, however, is not found as clearly ina different species, mice (230). The antagonist component is not strongenough to prevent some dependence in monkeys. In humans, alletorphinehas s~own ~ome success as an analgesic in postoperative abdominal surgery(eqUieffectlve at 1/20th the dose of morphine) and cancer patients(228,231).

Two well-studied 6,14-endoethenotetrahydrooripavine N-cycIopropyl-methyl analogs are alcohols with a methyl and an isoamyl substituent as R'(232). Codides and morphides having a large group at the C-19 position(e.g., n-butyl, isoamyl, cycIohexyl, phenethyl; see Table 3-19) demon-strate i?creasing analgesic potency, the bases being 50-500 times as potent asmorphl~e. The m~thyl analog (333) antagonizes morphine's analgesic anddepressive effects 10 the mouse, rat (analgesia antagonism is 35 times thatof nalorphi.ne), and dog, without any evidence of agonism. The isoamylanalog .va~les f.rom 250 to 1000 times the potency of morphine as ananal¥e.slc I~ mice, rats, guinea pigs, and dogs by intraperitoneal (ip)adm1OIstratIOn but shows species variation in effects differing from those ofmorphine.

FI III Diels-Alder Adducts of Thebaine 139

The 3-deoxy analogs, such as base 346 of N-substituted 6,14-endoethenooripavine alcohols that have antagonist properties, such as 337,show weaker antagonism than the 3-hydroxy counterparts and, in mostcases, show some weak analgesic activity. The 3-deoxy N-allyl andN-cycIopropylmethyl analogs (347, 348) of analgesic oripavine alcohols(339, 341) show decreased analgesic activity (226).

In the 6, 14-endoethano N-cycIopropylmethyl nororipavines, the primaryalcohol (349) and the diastereomeric secondary methyl alcohols (350, 351)are powerful antagonists with low intrinsic activity (28,228). Diprenor-phine (352) is not only a morphine antagonist in rats (tail pressure test) buthas over 300 times the potency of nalorphine, with no antinociceptiveactivity in mice (tail flick test) (Table 3-25). It is marketed as Revivon,which is used for reversal in game animals of the immobilization inducedby etorphine (316) (Immobilon). Diprenorphine in rats displays in vivobinding kinetics very different from those of pure agonists such asetorphine (224a). Although the cereberal receptor affinities of diprenor-phine and etorphine are in the 0.1-0.2 nM range, diprenorphine has a longin vivo receptor halt-life for dissociation (approximately 18 minutes), beingretained at several cereberal binding sites for many hours. In contrast, thehalf-life of etorphine is about 50 seconds. Antagonists are thus theorized tobe more effective than agonists in displacing tritiated opiate receptorligands in vivo.

Increasing the size of the alcohol alkyl substituent in the CPM oripavinesgives mixed agonist-antagonist activity, compounds such as 353 (n-propyl)and 354 (n-butyl) becoming powerful agonists instead of antagonists in therat tail pressure test. The partial agonist buprenorphine (355) (Temgesic),


Table 3-25

Analgesic Activity of 6,14-EndOethana N-CPM Orvinols

R'IIC~~RII

\OH

OCH3

Analgesia".b

Rat Tail Pressure Mouse Tail Flick

R' R"

349350351352'3533543551

HHCH3CH3CH3CH3CH3

HCH3HCH3(CH2hCH3(CHzhCH3C(CH3h

0.0250.0110.020.008 >IOOd

0.0080.0410.024

O.OOY

5.6

1.7

0.22

" Reference 228. b mg/kg, sc or ip. r Diprenorphine.d

EDso morphine = 1.8 mg/kg; EDS<Jnalorphine> 100 mg/kg.C ADso morphine> 100 mg/kg; ADS<Jnalorphine = 0.95 mg/kg.f

Buprenorphinc.

with a t-butyl group, has analgesic potency 25-75 times that of morphineand morphine antagonist potency 4 times that of nalorphine (233). It has arapid onset, produces a weaker physical dependence than morphine inrodents (233), has a longer duration of action than morphine in the rat tailpressure test, and has known metabolic degradation pathways (234),making buprenorphine useful in certain physical conditions in humans(235) in whom it is also effective by sublingual administration.

3, Acid-Catalyzed Rearrangements to Unsaturated Ketones The alco-hols of 6,14-endoetheno and 6,14-endoethano tetrahydrothebaines andoripavines are all unstable to acids and suffer dehydration and complexrearrangement, depending on the nature of the alcohol group, the 6,14-bridge, and the reaction conditions.

In summary, all C-19 alcohols (331) give phenolic ketones (356) asstable end products of acid-catalyzed rearrangement, the yields of theintermediate codeinones being very poor. These phenolic ketones are themajor end products of the 6,14-endoethano series and 6,14-endoethenophenyl derivatives. The 6,14-etheno alcohols of straight chain alkyls


356

331

R = H, CH3RI

= H, CN, alkyl, other

R' = R" = H, alkyl, aryl

X = C2H2, C2H4

R"

357Scheme 3-42. Acid-catalyzed rearrangement products of C-19 alcohols. Reagent: (a) acid

(e,g., formic, hydrochloric).

rearrange complet~ly to produce primarily cycIohexenodihydrocodeinonesof type 357 (Scheme 3-42). The 6,14-ethano alcohols having alkyl substi-tuents with chain branching adjacent to the alcoholic center rearrange inacid in a manner different from that of their straight chain counterparts(236).

Brief heating of these alcohols in formic acid initially produces theolefinic side chain product 358 (Scheme 3-43) rather than a C-7 olefin, asconfirmed by characteristic olefinic absorbances in the proton NMRspectrum (237). Diastereomeric alcohols at C-19 produce the same olefinicproduct, which is itself unstable in acidic media. The 6,14-endoethenoolefins of 358 rearrange with prolonged heating to 14-alkenyl codeinones(359), in accordance with their chemical properties and absorption spectra,

359 X C2H2

360 X = C2H4

Ie

142

331

358

\


368 R1 R = R' = CH3;

Rt' H; X = C2H2

362 X = C2H4

Scheme 3-43. Acid-catalyzed rearrangement to 14-alkenykodeinones and a,,B-unsaturated

ketones. Reagents: (a) formic acid; (b) hydrochloric acid, room temperature; (c) hydrochloricacid, heat; (d) sodium hydroxide. 2-ethoxyethanol; (e) hydrochloric acid; (f) zinc, acetic acid.

by protonation of the C-19 double bond followed by ring fission. Thedegree of substitution of the double bond determines the ease of this laterrearrangement to the codeinones, with either refluxing formic acid ordilute mineral acid being effective reagents. Again, diastereomeric alco-hols produce the same codeinone product. 14-Alkenyldihydrocodeinones

HI Diels-Aldcr Adducts of Thebaine 143

(360) are usually not easily produced from 6,14-endoethano alcohols dueto further rearrangements in acidic media, but they have been obtained bycatalytic or chemical (with sodium borohydride in pyridine) reduction ofthe 6, 14-endoetheno-14-alkenylcodeinones, for example, as in the casewhere the R"H2C group is phenyl (238).

If 14-alkenylcodeinone bases (359) [or the precursor 6,14-endoethenoalcohols (331), the C-6 hydroxy alcohols (361), and the side chainolefins (358)] are heated with hydrochloric acid, further rearrangementoccurs to C-4 phenolic O',,B-unsaturated ketone derivatives of structuraltype 356, isomeric with structure 359 and characterized by both protonNMR and UV spectroscopy (Scheme 3-43). The carbonyl (or its equiva-lent) at C-6 seems to be mandatory for this rearrangement, since it mayactivate the ether bridge. The 6-hydroxy base (361) is readily obtained withhydrochloric acid treatment at low temperature, but this can be subse-quently converted to the same C-4 phenolic base (195,237). In cases whereR' and R"H2C are different hydrocarbon chains, both cis and transgeometric isomers of 356 are obtained. These O',,B-unsaturated ketones canbe reduced to the saturated ketones (362) with zinc and acetic acid.

If the secondary and tertiary alcohols of 331 are first converted to thetosylates (207), and then either refluxed in xylene or treated withpotassium t-butoxide in boiling [-butanol, C-7 olefins (363), or terminalolefins (358), both with an intact 4,5-oxo bridge result (Scheme 3-44). Thismethod for forming 7-alkylidenes has been used for both 6,14-endoethenoand 6,14-endoethano tosylates when the two substituents on the C-19alcohol are hydrogens and methyl groups (239). Treatment of 6,14-endoetheno olefins (363) with perchloric acid leads directly to 0',13-unsaturated ketones (356). The 1,I-dimethyl olefin (364, R" = R' = CH3)and the un substituted olefin, the 7-methylene base (364, RII= R' = H),have been prepared by this route.

The C-4 phenolic O',,B-unsaturated ketones can also be obtained fromthe grignard reduction product of ketones (e.g., 282) by treatment withcold hydrochloric acid, these being milder conditions than those for thedehydration and hydrolysis of alcohols (331) to l4-alkenylcodeinones(Scheme 3-45) (201). Both the C-4 phenol and methyl esters of 356 havethus been prepared using this route.

Reaction of base-catalyzed rearrangement products such as 205 alsoprovides a route to C-4 phenolic O',,B-unsaturated ketone products.Reaction with methyl lithium to give an intermediate C-19 alcoholfollowed by hydrolysis with cold dilute hydrochloric acid to a C-4 phenolicketone (365) and then with hot hydrochloric acid yields the olefinic ketone356 (Scheme 3-45). The product is identical to that formed by acid-catalyzed rearrangement of l4-alkenylcodeine derivative 359 or of hydroly-sis of the alcohol grignard reduction product 282.


a or b)

+ 358

: ,R I

C'

Tsa~ \R"

331 363

R' R" = H, CH3

356

364 R" R' H or

R" R' CH]

Scheme 3-44. a,,8-Unsaturated ketones from 7-alkylidenes. Reagents: (a) refluxing xylene;(b) potassium t-butoxide, butanol; (c) perchloric acid, heat.

In the rearrangement of most I4-alkenylcodeinones (359), the 5,14-bridged C-3 phenols and methyl ethers of type 356 actually become theminor products of rearrangement and a competitive process produces themajor component as a nonphenolic, nonconjugated ketone. This stableend product can also be obtained directly from the 6,I4-endoetheno C-I9alcohols of type 331 when rearrangement is pushed to completion and isthe result of either stereoisomeric alcohol, due to an intermediate C-?carbonium ion formation. Thorough proton NMR studies and chemicaltransformation studies have determined the product to be cyclohexeno-[1' ,2':8,I4]dihydrocodeinones 357a and 357b formed by protonation of the

III Diels-Alder Adducts of Thebaine

y

282

R2 Rl = R = R' CH]; R" = H

b,a

y

145

356

R = R2 = H, CH3Rl H, CN, alkyl, othel

R' = R" - H, alkyl, ary

205 365R = Rl = R' - CH3

Scheme 3-45. a,,8-Unsaturated ketones from C-19 alcohols. Reagents: (a) hydrochloricacid, room temperature; (b) alkyl lithium; (c) hydrochloric acid, heat.

enone system of 366 [the proto tropic equilibrium product of 14-alkenylcodeinone (359)] and collapse of the carbonium ion intermediate(367) (the product of addition of the C-8 carbonium ion to the side chain)in one of two ways, depending on the nature of the substituents in theunsaturated ring (Scheme 3-46) (240,241). The structure of the rearrangedproduct has been subsequently confirmed by X-ray studies (242). In caseswhere R' and R" are alkyl groups, the ~5' isomer (357b) is usually favoredover the ~4' (357a). This rearrangement process is not operable in6,14-endoethano analogs due to the need for the enone system in theintermediates. 6,I4-Endoetheno bases that cannot isomerize to olefins(366), such as when R"H2C is replaced by phenyl, give rise only to the5,14-bridged phenols of type 356 (237,240).

146

359


a

367

366

357b

369 R1 = R" = R' = CH3;R = H, CH3

Scheme ].46. Synthesis of cyc1ohexenodihydrocodeinones and morphinones. Reagent:(a) formic or hydrochloric acid.

357a

Base~ of type 356, ~62, and 357 with substituents other than methyl ont~e tertiary nItrogen (I.e., H, CN, other alkyls) are prepared in moderateYield by rearrangement of the N-substituted alcohols of type 331. The3-hydroxy analogs of each can be obtained by demethylation of the3:methoxy rearrangement products using hydrobromic acid or by coin-billed rearrangement and demethylation of the C-19 alcohol thebaineadducts with the same reagent (237,240).

r III Diels-Alder Adducts of Thebaine 147

The biological activity of the two primary types of products resultingfrom acid-catalyzed rearrangement of C-19 alcohols, namely, bases 356and 357, has generally been disappointing. Although this transformationwould be expected to generate an analgesic, it produces opiate derivativesthat have no analgesic effects but that do have central antidepressant (243)as well as other central effects (244). The dehydration and rearrangementof the C-19 alcohols to the 14-alkenylcodeinones (359) results in asubstantial decrease in analgesic potency; however, some phenolic a,{3-unsaturated ketones (356) do have moderate potency. When R' is methyl,R" is hydrogen, and Rand R

I are methyl, the base 368 (Scheme 3-43) has 2times the potency of morphine and its C-4 methyl ether has 15 times itspotency (237). The cyclohexenodihydrocodeinones and morphinones havedecreased analgesic or antagonist activity compared to the C-19 alcoholprecursors. The cyclohexenodihydromorphinones are interesting, though,in that they represent the only N-methyl series of compounds in whichmorphine antagonism has been demonstrated. The 6,5' morphinone isomer(369) (R = H) has l/lOth the potency of nalorphine; the codeinone(R = CH3) is weaker (191).

14-AlkenyIcodeinones (359) and their dihydro derivatives (360) can bereduced at the C-6 carbonyl group with sodium borohydride to give the6-hydroxy analogs (237). Reduction of the codeinones gives exclusively6a-hydroxy products, whereas dihydrocodeinones give mixtures of theisomeric 6a and 6{3alcohols (dihydrocodeines and dihydroisocodeines),the ratio being solvent dependent (238). Reduction of the carbonyl groupin the cyclohexenodihydrocodeinone and dihydromorphinone derivativesof 357 produces the 6a-hydroxy products (240).

4. Modifications and Derivatization In an effort to increase theanalgesic potency of the C-19 alcohols of the 6,14-endoetheno-tetrahydrothebaines and oripavines, modification of the aromatic ring hasbeen studied. Addition of substituents to the aromatic A ring of dimethylalcohol (281) causes either a loss or a reduction of activity in the resultingcompounds compared to their unsubstituted analogs. The phenol andmethyl ethers of the chlorinated derivative 370 are less active than theunsubstituted precursor; the phenolic amines, derivatives 371, also havegreatly reduced analgesic activity (245).

Modification of the piperidine ring by substitution at the carbon adjacentto the nitrogen (C-16) has also been achieved. The 15,16-unsaturated6,14-endoethenotetrahydrothebaine and oripavine precursors result fromdehydration with mercury (II) acetate (246). N-substituted analogs canalso be dehydrogenated to enamines if they do not contain a reactive olefin;the 6,14-endoetheno bridge always remains inert. The enamines can bereduced back to the parent bases with sodium borohydride, providing a

R1 R2 H.:CH3

IPC --R'

\'H 372 R' n-butylCH3 373 R' Cyclohexyl

R2

-S;H] R2 = CH)

-'IIC_R'

bH 374 R' CH2C6H5

CH3 375 R' Cyclohexyl

148 ] Synthesis of Morphine, Codeine, and Related Alkaloids

convenient method for selective C-15 labeling with tritium or C-15, C-16radiolabeling (246,247). Treatment of the enamines with acid yieldsiminium salts (i.e. perchlorates), which, in additi~n to the 15,16-unsaturated compounds, then serve as intermediates for C-l5, C-l6substituted derivatives (248). The 16-alkyl and 16-aryl derivatives ofanalgesics in the 6,14-endoethenotetrahydrothebaine series have beenprepared by reaction of these iminium perchlorates with grignard reagentsor lithium alkyls (249). Other derivatives of both C-15 and C-16 6,14-saturated and unsaturated bridge compounds have been made by thesemethods.

The C-15-C-16 modification has not been successful in producinganalgesics. 15,16-Unsaturated carbinols, such as 372 and 373, are less

y"CH]

"'C - CH]'OH

OCH]

370

371

R H, CH]; Y H; X = Cl

R = H; X = H; Y = CH2Y' where


potent analgesics than the parent saturated bases in the rat tail pressuretest. Compound 373 has only about 1/4000th the analgesic potency of itsparent, although it has potent antitussive activity (246). Unsaturatedanalogs with substituents other than hydrogen at C-l6 also show littleanalgesic activity. The 6, 14-endoethano and 6,14-endoetheno-tetrahydrothebaines bearing C-15 and/or C-l6 substituents have allshown little activity as analgesics, although substitution at C-16 withan alkyl group has led to potent antitussives. 16a-Phenyl, benzyl,phenethyl, and alkyl other than methyl in the etheno series completelyeliminate analgesic activity in C-19 alkyl and aryl carbinols. A 16a-methylsubstituent retains marginal activity in some of the more potent carbinols,for example the benzyl carbinol (374), which is 750 times less active thanthe unsubstituted base but is only 4-5 times less active than morphine(249). The 16-methyl cyclohexyl carbinol (375) has no analgesic activitybut has 12 times the potency of codeine as an antitussive (250). Increasingthe chain length at C-16 to ethyl decreases antitussive activity by a factor of3. Continued increase in the alkyl chain shows further reduction, with the16-phenyl analog being inactive.

Various analogs in the 7,B-carbinol series have been prepared to checkanalgesic potency in comparison to the 7a-equivalents (241). For exam-ple, starting with 7-methyl-epi-nepenthone derivatives 376 and 377, thetertiary alcohols (378-380) result from treatment with the appropriategrignard reagent where the chiral products have the S-configuration atC-l9 (Scheme 3-47). The C-19R secondary alcohols 381 and 382 resultfrom treatment with sodium borohydride. The analgesic potencies of theseC-19 carbinols vary, showing a strong dependence on the C-19 configura-tion. The secondary alcohols 381 and 382 have 40 and 6 times the potencyof morphine in the rat tail pressure test, respectively, but the tertiaryalcohol 378 has only one-third morphine's potency. The N-CPM methylalcohols, 380 and 382, have no antagonist activity.

A series of related C-7 tertiary alcohols where the hydrocarbon chain isdirectly attached to C-7 have been prepared by appropriate grignardreaction with the 7-oxotetrahydrothebaine (191) (Scheme 3-48) (251).Attack from the a-face is preferred on steric grounds, approach of reagentfrom the ,B-face being hindered by the C-5 and C-15 ,B-hydrogens. Theisolated products have an H-5,B proton signal at ~4.5 ppm, attributable tothe 1,3 deshielding by the 7,B-hydroxyl group, thus allowing assignment oftheir structures.

In those compounds where the hydroxyl is directly attached to C-7instead of C-19, the effects on analgesic potency observed in a homologousseries directly parallel those in the C-19 carbinols, although relativecomparative potency is significantly diminished. Derivatives of 383 are less

CH3

191 383 R'

384 R'

384c R'

150 3 Synthesisof Morphine, Codeine, and Related Alkaloids

R R'

378 CH]

379 CH]

380 CPM

376 R = CH3

377 R = CPM

:CH3}6HS

'-C'-H\OH

OCH3

381 R = CH]

382 R = CPM

Scheme 3-47. Synthesis of 7j3-carbinols. Reagents: (a) grignard reagent; (b) sodium

borohydride.

potent than morphine; the alcohols of 384 show a lO-fold increase inanalgesic potency from phenyl to benzyl or phenethyl. The phenethyl andphenpropyl analogs (384c, 384d) are the most active, being about threetimes as potent as morphine.

5. Stereochemical Assignments Proton NMR spectroscopy, includingthe special techniques mentioned earlier for obs.erving spin systems andcoupling constants, has definitively charactenzed th~ 7a.- and 7f3-

carbinols of Diels-Alder adducts of thebaine and their aCid-catalyzedrearrangement products. The epimeric C-7a compounds have NMRspectra analogous to those described earlier for C-? ketones and esters(Section III,A,5, Fig. 3-1).


a

CH3, n = 0-2

C6HS' n 0-4

C6HS' n 2

384d R' C6HS' n 3

Scheme 3-48. Synthesis of 7a-substituted-7j3-alcohols. Reagent: (a) grignard reagent.

(A) (B)

R configuration S configuration

Fig. 3-2.

NMR and IR spectroscopies have also provided a basis for assigning theconfiguration at the C-19 asymmetric center (219). The physical method-ology results are consistent with the experimental ones, showing that thesynthesis of C-19 alcohols is stereoselective. For the two epimers where thesubstituents are phenyl and methyl (A and B, Fig. 3-2), the tertiaryhydroxyl resonances at 5.26-5.8 ppm (CDCI]) indicate intramolecularhydrogen bonding, also confirmed by the IR spectra, thereby placing thetertiary hydroxyl near the C-6 methoxyl group. Both diastereomers showrestricted rotation about the C-19-C-? bond. In A the olefinic protonsshow marked upfield shifts, indicating the proximity of phenyl to the endobridge. This results in a shielding effect (this effect being stronger for thecloser C-1S than for the C-1? proton) and characterizes the R epimer.By comparison, then, B has the S configuration at C-19. The H-5f3chemical shift is consistent with earlier work on C-? ketones, indicating


(A) (B)

Fig. 3-3.

that the compounds are 70: epimers, the configuration at C-7 remainingunchanged through synthesis.

The proton NMR spectra for the acid-catalyzed rearrangement productsdihydrocyclohexenocodeinones show the C-5 proton characteristic of thecyclic ether bridge at -4.5 ppm. No olefinic endo bridge proton signals areapparent. The isomers are easily distinguished when R' is phenyl and R" ishydrogen in compounds 357a and 357b (A and B, Fig. 3-3). Even thoughboth contain the styrenoid system and have styrenoid ultraviolet absorp-tion, spin-decoupling techniques indicate that one of the methyleneprotons of A adjacent to the double bond at position 3' has a down fieldshift characteristic of being allylic and of being located near the unsharedelectron pair on nitrogen (240). When both R' and R" groups are alkyl, thelack of an olefinic proton signal characterizes the 6.5' isomer (B).

Further NMR experiments on the carbinols has confirmed that thedifference in H-80: and H-8,8 chemical shifts is partly due to effects of thering nitrogen, although both C-8 protons have their chemical shifts affected(upfield shifts) by the C-17-C-18 double bond. H-9,8 and N-methylprotons consistently appear downfield. The 6,14-endoethano carbinolshave provided evidence for the double bond deshielding of H-9,8, sincethe saturated analogs consistently have H-9,8 0.5 ppm upfield from itsaverage chemical shift at 3.13 ::t 0.04 ppm (219). Various competingeffects, however, have made a complete analysis of the geminal80: and 8,8protons in some systems impossible, even though the effects produced bythe nearby tertiary nitrogen and C-17-C-18 double bond are consistent(219).

The entire molecular structure of one Diels-Alder adduct, etorphine,has been elucidated through X-ray crystallographic analysis of the hydro-bromide salt (252). This comprehensive study of the subtle details ofgeometry has supplemented the NMR spectroscopic studies.

C. Opiate Receptor Probes

Several Diels-Alder adducts of thebaine and oripavine have been usedas opiate receptor probes (253) in the hopeof defining a three-dimensional

III Diels-Alder Adduets of Thebaine 153

receptor model. The extremely potent analgesic activities of the C-7substituted alcohols of the 6,14-endoetheno and 6,14-endoethano Diels-Alder adducts of thebaine, influenced by the size, nature, and configura-tion of ~he.alco.holic portion, suggested to Bentley and Hardy (222) thatBeckett s sImplIfied model (254) of the morphine receptor (three points:anionic, planar, and cavity) might be extended (255) to include additionalsignificant points of attachment by these bases. This fourth binding site forthe group at C-7 would have configurational selectivity for the C-19alcohols.

The first sugg.estion by Bentley and Lewis that the alcoholic hydroxylgroup ~as reqUIred as a. specific binding site was disproved by the highanalgesIc potency (1000 tImes that of morphine) found in the cyclohexano-derivative (385). Subsequently, the presence of a lipophilic site on thereceptor that could mediate analgesic effects by interaction with the alkyland phenyl groups on C-19 (256) and that could discriminate betweendiasteromers was proposed. In support of this idea, the phenethyl carbinol(302) (PET, analgesic potency 500 times that of morphine; Table 3-19)supposedly owed its increased activity to the presence of the additionalphenyl g~ou~ (257). In addition, destruction of the aromatic A ring byozono~ysls dId not. produce a complete loss of activity in the resultinglactomc esters, whIch cannot adopt a topological arrangement isostericwith the mo~phine aromatic nucleus (257) and yet have an analgesicpotency eqUIvalent to that of morphine. Looking at a series of 6-demethoxy thevinols and orvinols, Rapoport et ai. (258) demonstrated thatth~ hydrogen bond between the C-6 methoxyl and the alcoholic hydroxyl(FIg. 3-2), as supported by quantum mechanical calculations, NMR spec-tro~c?py, and X-~ay. crystallography, was not essential for analgesicactIvIty. The specIficity for the C-19R absolute configuration, however,sug~ested to them a secondary binding site that had a high discriminatoryaptitude in the lipophilic region of the receptor.

On the basis of this modified model for the opiate receptor, Michne et ai.(259,260) investigated a series of 2,6-methano-3-benzazocine-ll-propanols(386), resembling various agonists and agonist-antagonists, that shouldhave been capable of the proposed four-point receptor interaction, sincet?e compounds have an appropriately substituted nucleus and an asymmet-ncally substituted alcohol approximating that of the Diels-Alder adductalcoho.ls. In these compounds, the classical structure-activity profile forna.rcotlc agonist and antagonist activities, as seen in bridged thebaine and?npavine derivatives, has not been upheld. Interestingly, though, the twoIsomers of 387 having an isoamyl alcohol substituent at CAll are three andfive times as potent as nalorphine as antagonists (261). In Diels-Alderadducts of a simpler bicyclodecane skeleton (388, 389), Crabb and

r-'\' CH3

385HO R1

386R1 Me, Et, n-Pr, n-Bu, t-Bu,

R2 Me, CPM, R3 = H, Me;

R4 Me, Et

387 R1 i-Am; R2 = R4 CH3, R3 H


HO

388 389

Rl = R2 0= H, C Me, C02Et, CN

Wilkinson (262) demonstrated for most compounds studied a loss ofanalgesic potency accompanied by toxic side effects. This led them toquestion earlier hypotheses and to believe that the aromatic ring of thebridged thebaine compounds is actually a structural requirement.

IV. The Chemical Anatomy of Morphineand Its Derivatives

A. The Chemical Anatomy of Morphine

Natural morphine is a levorotatory molecule containing five rings. Onthe basis of the SAR results presented in Section II,A, the followinggeneralizations can be made (see Fig. 3-4):

1. Enantiomeric dextrorotatory morphine is devoid of analgesic activity.2. A trans-ring junction between rings Band C drastically reduces

analgesic potency.

IV The Chemica! Anatomy of Morphine and Its Derivatives 155

..CH.. CO. CHOH

phenyl. thienyl +---~ X ::~H.furyl "-

,/IN

D

+H,OHorO,CRatC-14

___ ____+ ;:. 7 (8). ~- CH, Or CH. CH, at C- 8

,,, C un.;:. 6 (71 or {J- (CH.)n C.H.

H OrCOR'" -- -0 0",',

J H. OH, O,CR. = 0, alkyl, OCH, at C-6

, CH,at C-5

Fig. 3-4. Potency-enhancing substituents on morphine. (This representation is adapted fromthat reproduced in ref. 30.)

3. A phenolic hydroxyl at C-3 is important for analgesia, but notnecessary. The 3,6-deoxy-derivative is equipotent to morphine butmay represent metabolic hydroxylation.

4. Other substituents on the A-ring decrease or eliminate activity.5. Substituents at C-lO in the B-ring maintain or decrease morphino-

mimetic activity.6. Some of the chemical features of the Coring of morphine are

relatively noncrucial: removal of the double bond [7(8)] or thealcohol at C-6. Numerous other chemical modifications are alsocompatible with enhanced analgesic activity: a C-5 methyl group,oxygenation or alkylation at C-6, phenylalkyl substitution at 7f3, andshort alkyl substitution at 8f3. '\

7. Hydroxyl substitution at the BC-ring junction (C-14), as well as itsacyl derivatives, strongly enhances analgesia. Other substituentseliminate activity.

8. The methyl group on the amine is not optimal. Replacement byaralalkyl or functionalized aralalkyl groups increases morphinomime-tic activity severalfold. Replacement by N-lower alkyl (propyl, allyl,cyclopropylmethylene) produces morphine antagonists.

9. Addition of a sixth ring by Diels-Alder additions to thebaine canincrease either morphine agonist or antagonist activity by at least fourorders of magnitude.

B. The Chemical Anatomy of Diels-Alder Adducts

Diels-Alder adducts of thebaine and their analogs, having greatercomplexity and rigidity than morphine, as well as a different shape, have

156 3 Synthesis of Morphine, Codeine, and Relattd Alkaloids

alkyl. substituted alkyl. alkenyl

H or COR.R =alkyl

-+ n- or IJ. CH(OH)R'; tr- or7 fJ-C(OH)R'R" where R'=CHJ and

OCHJ R"=(CH2)nCHJ or(CH2)nAr

R configuration preferred

Fig. 3-5. Potency-enhancing substituents on the Diels-Alder adducts.

been used in attempts to test receptor criteria for analgesic activity and theseparation of desired from undesired biological effects in an effort to createa superior morphine. These Coring-bridged compounds have exhibited awide range of agonist -antagonist profiles (228,229); however, the only twomodifications creating dramatic increases in biological activity are (a)demethylation at C-3 to the oripavine base and (b) substitution at C-7 withsecondary and tertiary alcohols. SAR in the carbinol series is complex, butthe physiological activity of each base is dependent on the nature of thesubstituents on the C-3 oxygen atom, the nature and size of the alcoholicgroup, and the substituent on the nitrogen atom, with the following trendsbeing observed (191,263) for these structures (Fig. 3-5):

1. The substitution on the carbinol group at C-7 is important: C-19tertiary alcohols have a higher analgesic potency than secondaryones; however, in cases where both C-7a and C-7{3 epimers havebeen evaluated, only slight differences in potency have been observedin the pairs.

2. Highest activities have been found when a moderate disparity in sizebetween the two groups on the C-19 alcohol, R" and R', exists. Onesubstituent should be small, that is, H or CH3. Maximal analgesicactivity is then found when the second substituent is a 3- to 5-hydrocarbon chain; further lengthening results in a steady decrease inactivity.

3. The diastereomers of unsymmetrical tertiary alcohols can showmarkedly different analgesic properties, the 19R configuration beingthe more potent morphine agonist.

4. The comparable 6, 14-endoetheno and 6,14-endoethano analogs showonly marginal differences in analgesic agonist or antagonist potency.

5. The oripavine derivatives (C-3 hydroxyl) or their C-3 acetylatedanalogs are more potent analgesics than the thebaine bases (C-3methoxy).

References 157

6. The piperidino nitrogen should be tertiary, the secondary aminesbeing less active as agonists. Increasing the size of the nitrogensubstituent beyond methyl steadily decreases analgesic activity. SomeN-allyl and N-cyclopropylmethyl thebaine and oripavine derivativesof tertiary alcohols are potent antagonists.

7. The piperidine and ether rings should remain intact. Substitution onthe piperidine ring near the basic nitrogen creates potent antitussives.

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225b. H. E. Dobbs, G. F. Blane, and A. L. A. Boura, Eur. J. Pharmacal. 7, 328 (1969).226. J. W. Lewis and M. J. Readhead, J. Med. Chem. 16, 525 (1970).227. K. W. Bentley, U. S. Patent 3,433,791 (1969); Chem. Abstr. 70, 78218s (1969).228. J. W. Lewis, Adv. Biochern. Psychopharmacol. 8, 123 (1973).229. G. F. Blane, A. L. A. Boura, E. C. Leach, W. D. Gray, and A. C. Osterberg, J.

Pharm. Pharmacal. 20, 796 (1968); G. F. Blane and D. S. Robbie, in "Agonist andAntagonist Actions of Narcotic Analgesic Drugs" (H. W. Kosterlitz, H. O. J. Collier,and J. E. Villarreal, cds.), pp. 120-127. Univ. Park Press, Baltimore, Maryland, 1973.

230. J. D. Bousfield and J. M. H. Rees, J. Pharrn. Pharmacal. 21, 630 (1969).231. J. T. Macbeath and B. A. Moore, Br. J. Anaesrh. 48, 97 (1976).232. K. W. Bentley, A. L. A. Boura, A. E. Fitzgerald, D. G. Hardy, A. McCoubrey, M. L.

Aikman, and R. E. Lister, Nalure (London) 206, 102 (1965).233. J. Dum, J. Bliisig, and A. Herz, Eur. J. Pharmacal. 70,293 (1981); A. Cowan, J. W.

Lewis, and 1. R. Macfarlane, Br. J. Pharmacal. 60, 537 (1977).234. M. J. Rance and J. S. Shillingford, Biochem. Pharmacal. 25, 735 (1976).235. J. H. Mendelson, J. Ellingboe, N. K. Mello, and J. Kuehnle, J. Phannacol. Exp. Ther.

220, 252 (1982).236. K. W. Bentley, D. G. Hardy, B. Meek. J. B. Taylor, J. J. Brown, and G. O. Morton,

J. Chem. Soc. C p. 2229 (1969).237. K. W. Bentley, D. G. Hardy, and B. Meek, J. Am. Chem. Soc. 89, 3293 (1967).238. J. W. Lewis and M. J. Readhead, Telrahedron 24, 1829 (1968).239. J. W. Lewis and M. J. Readhead, J. Chem. Soc., Perkin Trans. I p. 881 (1972).

l

References [65

240. K. W. Bentley, D. G. Hardy, C. F. Howell, W. Fulmor, J. E. Lancaster, J. J. Brown,G. O. Morton, and R. A. Hardy, Jr., J. Am. Chem. Soc. 89, 3303 (1967).

241. J. W. Lewis and M. J. Readhead, J. Chem. Soc. C p. 2296 (1971).242. A. A. Freer, G. A. Sim, 1. G. Guest, A. C. B. Smith, and S. Turner, J. Chem. Soc.,

Perkin Trans. 2 p. 401 (1979).243. A. Cowan and B.A. Whittle, Br. J. Pharmacal. 44, 353P (1972); N.S. Doggett,

H. Reno, and P. S. J. Spencer, ibid. 50, 440P (1974).244. A. Cowan, Fed. Proc., Fed. Am. Soc. Exp. Bioi. 40, 1497 (1981).245. K. W. Bentley, J. D. Bower, and A. C. B. Smith, J. Chem. Soc. C p. 2241 (1969).246. D. 1. Haddlesey, J. W. Lewis, P. A. Mayor, and G. R. Young, J. Chem. Soc., Perkin

TraIlS. I. p. 872 (1972).247. J. W. Lewis, M. J. Rance, and G. R. Young, J. Med. Chem. 17,465 (1974).248. D. 1. Haddlesey, J. W. Lewis, and P. A. Mayor, J. Che,iJ. Soc., Perkin Trans. I p. 875

(1972). '249. J. W. Lewis, P. A. Mayor, and D. 1. Haddlesey, J. Med. Chem. 16, 12 (1973).250. A. L. A. Boura, D. 1. Hadd[esey, E. J. R. Harry, J. W. Lewis, and P. A. Mayor,

J. Pharm. Pharmacal. 20,961 (1968).251. J. W. Lewis and M. J. Readhead, J. Med. Chem. 16, 84 (1973).252. J. H. van den Hende and N. R. Nelson, J. Am. Chem. Soc. 89, 2901 (1967).253. D. H. Thorpe, Anesth. Analg. (Cleveland) 63, 143 (1984).254. A. H. Beckett and A. F. Casey, J. Pharm. Pharmacal. 6, 986 (1954).255. P. S. Portoghese, J. Med. Chem. 8, 609 (1965).256. H. F. Fraser and L. S. Harris, Annu. Rev. Pharmacal. 7, 277 (1967).257. K. W. Bentley, D. G. Hardy, and P. A. Mayor, J. Chem. Soc. C p. 2385 (1969).258. C. W. Hutchins, G. K. Cooper, S. Piirro, and H. Rapoport, J. Med. Chern. 24,773

(1981).259. W. F. Michne, R. L. Salsbury, and S. J. Michalec, J. Med. Chem. 20, 682 (1977).260. W. F. Michne, J. Org. Chem. 41, 894 (1976).261. W. F. Michne, J. Med. Chem. 21, 1322 (1978).262. T. A. Crabb and J. R. Wilkinson, J. Chem. Soc., Perkin Trans. I p. 644 (1976).263. K. W. Bentley, Endeavor 23,97 (1964); K. W. Bentley and J. W. Lewis, in "Agonist

and Antagonist Actions of Narcotic Analgesic Drugs" (H. W. Kosterlitz, H. O. J.Collier, and J. E. Villarreal, cds.), p. 7. Univ. Park Press, Baltimore, Maryland, 1973.

264. E. F. Hahn, Medicinal Res. Rev. 5, 255 (1985).265. T. R. Burke, Jr., K. C. Rice, and C. B. Pert, Heterocycles 23, 99 (1985); M. A.

Channing, W. C. Eckelman, J. M. Bennett, T. C. Burke, Jr., and K. C. Rice, 1m. J.Appl. Radial. Isol. 36, 429 (1985).

266. C. B. Peat, J. A. Danks, M. A. Channing, W. C. Eckelman, S. M. ,Izrson, J. M.Bennett, T. R. Burke, Jr., and K. C. Rice, FEBS LeU. 177, 281 (1984).

267. 1. lijima, J. Minamikawa, A. E. Jacobson, A. Brossi, K. C. Rice, and W. A. Klee,J. Med. Chem. 21, 398 (1978).

268. M. Erez, A. E. Takemori, and P. S. Portoghese, J. Med. Chern. 25,847 (1982); P. S.Portoghese, and A. E. Takemori, Life Sci. 36, 801 (1985).

4.Physical Chemistry, Molecular Modeling, and QSARAnalysis of the Morphine, Morphinan, andBenzomorphan Analgesics

I. Physicochemical Studies. .A. X-Ray CrystallographyB. Proton NMR . . . . .C. Carbon-13 NMR . . .D. Dissociation Constants and Panition Coefficients

II. Molecular Modeling and OSAR StudiesA. Molecular Modeling.B. OSAR StudiesReferences . . . . . .

166167170172173174174183185

I. Physicochemical Studies

Physicochemical measurements have played a major role in assessing thestructure, configuration, conformation, and physical behavior of opiateanalgesics. X-Ray crystallography and nuclear magnetic resonance (NMR)spectroscopy have been used extensively. Other methods, such as infrared(IR), optical rotatory dispersion (ORO), circular dichroism (CD), andmass spectra, as well as partition coefficient and dissociation constant(pKa) measurements, have also found some application.

X-ray crystallography has been of particular value in studying semirigidopiates such as the morphine series, where the solid-state structure may beexpected to resemble closely the biologically active conformation. Formore flexible compounds, such as the arylpiperidines and methadoneanalogs, NMR has been used to assess solution conformation under avariety of conditions of solvent, temperature, and pH. IR spectroscopy hasbeen employed in studying intramolecular hydrogen bonding in the flexibleopiates. ORO and CD are potentially useful in the study of chiralcompounds, but most reports to date have simply interpreted spectra interms of known structural features. Measurements of partition coefficientsand pKa values have been carried out with the hope of relating theseproperties to in vitro and in vivo activity as well as examining possiblemechanisms of action. The following discussion focuses on the applicationof physicochemical methods to the study of compounds in the morphine,morphinan, and benzomorphan series.

166

I Physicochemical Studies 167

A. X-Ray Crystallography

Mackay's and Hodgkin's crystallographic study of morphine (1) in 1955played a key role in elucidating the structure of this substance (I). Sincethen, numerous compounds in the morphine series have been studied by

morphine codeine

this method. Kartha et al. (2) determined the absolute configuration of themorphine skeleton in their 1962 study of codeine (2).

Table 4-1 lists the morphine derivatives for which X-ray crystalJographicstudies have been reported. All of these compounds have in common a Tshape in which rings A and B constitute the vertical part of the T, and ringC and the piperidine ring represent the horizontal portion. The piperidinering is in a chair conformation, with the N-substituent equatorial for alJ ofthese compounds. N-Methylnalorphine (3) has a quaternized piperidine

Table4-1

X-Ray Crystallographic Studies of Morphine-Type Compounds

Compound CoRing Conformation References

Morphine (I)

Codeine (2)

N-Methylnalorphine (3)

Nalorphine (4)

Oxymorphone (5)

Naloxone (6)

7

3-Hydroxylevallorphan (8)

Azidomorphine (9)

14- HydroxyazidomorphineDextromethorphan (10)

Nalbuphine (11)

19- Propylthevinol (12)6-Acetyl-l-iodocodeine

13

1,4-62378,910,111213141516/7/8/920

BoatBoatBoatBoatChairChairChairChairChairChairChairBoatBoatBoat-Planar

168 4 Benzomorphan Analgesics

HO

-tN-CH2-CH=CH2I

CHJ

1N-methy1-na1orphine

!!

nalorphine

nitrogen; the active (opiate antagonist) isomer has an axial methyl groupand an equatorial allyl substituent (3). The isomer having an equatorialmethyl and an axial allyl group is inactive, suggesting that the N-allyl groupmust be in the equatorial position in order for the compound to be active asan antagonist. The Coring conformation of these compounds is dependenton the presence or absence of a 7,8-double bond and on the stereo-chemistry of the 6-substituent. Compounds such as morphine (1), codeine(2), and nalorphine (4) exhibit a Coring boat conformation (1-7,19); the6-a-substituent is in a bowsprit position. Coring saturated compoundshaving a 6-keto group [oxymorphone (5), naloxone (6), and the 8, 14-buteno

2 2oxymorphone naloxone

1 8


derivative (7)], a 6,B-substituent [3-hydroxylevallorphan (8) and azido-morphine (9)], or no 6-substituent [dextromethorphan (10)] exist in aCoring chair conformation, with 6,B-substituents equatorial (8-16). Nal-buphine (11) has a saturated Coring, but its 6-substituent has a stereo-chemistry; its Coring has a boat conformation with the 6-hydroxy group in abowsprit position (17). 19-Propylthevinol (12) has its Coring held rigidly ina boat conformation by the 6,14-ethano bridge (18). The 8-bromo-6,7-unsaturated compound 13 has a nearly planar Coring, with the exception ofcarbon atom 14 at the B-C ring junction (20).

2 10

HO

N -CHzO

CHJ:

HO -q ... CH2-CH2-CHJ

CHJ

11 12

nalbuphine

19-propylthevinol

11


B. Proton NMR

Proton NMR has been used to study the Coring conformations ofnumerous compounds in the morphine series (21-24). The NMR resultsare consistent with and extend the X-ray crystallographic findings (seeabove). In general, the following conclusions may be drawn from H-Hcoupling constants, chemical shifts, and shielding of 3- and 6-acetoxygroups:

1. When the Coring is saturated, it exists in a chair form.2. When there is a 7,8-double bond [e.g., morphine (1)], the Coring

exists in a boat or half-boat conformation.3. When there is an 8,14-double bond [e.g., neopine (14)], the Coring

exists in a half-chair conformation.4. When the Coring is a 6,7,8,14-diene [e.g., thebaine (15)], the C-ringis

essentially planar.

In the B-C trans-fused morphine system (16), the saturated Coring isforced into a boat or skew-boat conformation (24).

Proton NMR was used extensively by Fulmor et al. to determine thestereochemistry and configuration of several 6,14-endo-ethenotetrahydro-thebaine compounds (25). In the case of compound 17, the stereo-chemistry of the cyano group was determined by examining long-rangecouplings of the olefinic protons. In compound 18, NMR and IR spectrashowed that the C-19 hydroxyl group is hydrogen-bonded to the 6-methoxygroup in both stereoisomers; stereochemistry at C-19 could be assigned onthe basis of the observation that in one isomer the 19-phenyl group canshield the olefinic proton resonances by 0.5-0.6 ppm relative to the otherisomer.

14neopine

1.2

thebaine

Brine et al. reported that both 6a- and 6{3-naltrexol (19) and theirmono- and diacetates exist in a Coring chair conformation (26). For the 6{3compound, a chair conformation with an equatorial hydroxyl group is


CN

16

B/c t~ns-morphine

11

HO

N-CH~

126a-na1trexo1. R1 = OH. R2

6p-na1trexo1. R1 = H. R2

na1trexone. R1R2 = 0

consistent with other NMR and X-ray results; for the 60' compound, aboat conformation might be anticipated on the basis of the X-ray study ofnalbuphine (17). Brine et al. noted changes in the H-H coupling constantsand 13CNMR signals, which they attributed to an intramolecular hydrogenbond between the axial 6-hydroxy and the 3-acetoxy group. This hydrogenbond can be formed only when ring C is in a chair conformation.

For the spiro-oxirane derivative 20, Jacobson et al. used the couplingconstants and the nuclear Overhauser enhancement between olefinic andoxirane protons to assign the configuration at C-6 of the compound, asshown (27). In addition, they showed that the Coring exists in a boatconformation with the oxirane oxygen in a flagpole position. Proton NMRcoupling constants and chemical shifts were also used by Jacobson andco-workers to determine the positions and configurations of the halogen-ated morphine derivatives 21 and 22 (28).

HOH


HO

20

21

c:r-ch1oromorphide22

/1-ch1oromorphide

Using 600 MHz proton NMR, Glasel demonstrated nitrogen inversion inmorphine (29). At low pH, a small amount of N-axial methyl was detectedwith slow interconversion to the N-equatorial form. The axial form wasestimated to be about 1 kcaljmole less favorable than the equatorial form.The interconversion rate at neutral pH was found to be about equal to theNMR time scale, many orders of magnitude slower than the on-rate to thereceptor. Thus, the N-axial conformation should be considered as apossible receptor-active conformation.

C. Carbon-13 NMR

Carbon-13 NMR has not been used to any appreciable extent indetermining conformation or configuration in the morphine series. Most ofthe. carbon NMR literature for these compounds reports spectra andassIgns the resonances (30-32). Carroll et al. interpreted their carbon-13NMR results to mean that 6,14-endo-ethano compounds such as 19-propylthevinol (12) have A-, B-, and D-ring conformations similar to thoseof morphine (32).

Hexem et al. reported the high-resolution carbon-13 NMR spectrum ofcrystalline morphine sulfate (33). The spectrum exhibits resolved res-onances for each of the 17 carbon atoms. Each of the carbon atoms boundto nit.rogen exist.s. as an asymmetrical doublet, due to I4N_I3C dipolarcouplIng. In addItIOn, the signal for C-lS exists as a nearly symmetricaldoublet. These authors suggested that C-1S (part of the D-ring) may exist


in two different environments. Subsequently, the X-ray crystal structure ofmorphine sulfate was determined by Wongweichintana et al. (6); theyfound no evidence of disorder at C-15. The cause of the split signal for C-1Sunder these conditions is still not resolved.

D. Dissociation Constants and Partition Coefficients

Dissociation constants (pKa) and partition coefficients are physico-chemical properties related to the ability of drugs to pass through lipidmembranes. For example, Kutter et al. showed that intravenously, etor-phine (23) is 3800 times as potent as an analgesic as dihydromorphine (24);intraventricularly, it is only 40 times as potent (34). This result is attributedto the higher lipid solubility of etorphine, which facilitates its diffusionacross the blood-brain barrier. Since only the neutral (un-ionized) form ofthe molecule is likely to diffuse readily through lipid membranes, the pKamay have considerable influence on the ability of opiates to reach centralreceptor sites. Kaufman et al. determined the pKa values for a set of 15

CHJO:

CHJ - C -CH2-CH2-CHJI

OH

netorphine

214

dihydromorphine

opiate agonists and antagonists from several structural classes (35). Inaddition, they measured octanol-water distribution coefficients for thesecompounds at two temperatures (20° and 37°C) and at several pH values.Distribution coefficients increased with temperature, the magnitude of theincreases ranging from 21 to 200%. These authors noted that distributioncoefficients may be extremely sensitive to pH for amines that have pKavalues near physiological pH. They point out that physiological pH, whichis considered to be 7.4, may in fact range from 7.1 to 7.7, resulting in a300-400% difference in distribution coefficient for many opiate com-pounds. Since the normal pH of the fetus is 7.2, opiates tend to accumulateon the fetal side of the placental barrier.


II. Molecular Modeling and QSAR Studies

The div~rsi~y of chemical structures that are active narcotic analgesicshas made It dIfficult to construct a general structure-activity relationship(SAR). Most opiate agonist and antagonist SAR data are based onmorphine and structurally related rigid and semirigid analogs. Thus, it isnot surprising that most molecular modeling and quantitative structure-activity relationship (QSAR) studies of opiates have involved the mor-phine family.

A. Molecular Modeling

Morphine and structurally related cyclic analgesics, as well as opiatesthat have only a single ring in common with morphine, share a commonoverlap of the phenyl ring and the amine nitrogen. Beckett and Casy (36)have proposed these two common substructures as a basis for constructinga common pharmacophore. The pharmacophore can be described as a4-phenylpiperidine in the chair conformation with the phenyl ring in theaxial position (Fig. 4-1).

This model has two limitations. First, potent azabicycloalkanes (25) arerestricted to the equatorial form (37), and unrestricted 4-phenylpiperidines(see Chapter 8) are generally most stable in the equatorial state. Second,compounds like etonitazine (26) and fentanyl (27) are 100-10,000 times aspotent as morphine but do not exhibit an isomorphic chemical connectiv-ity relationship to morphine.

. 26

II Molecular Modeling and QSAR Studies 175

ojfFig. 4-1. The morphine structural pharmacophore.

Ofri~ ~.....I .~._.~

:'~

~

Fig. 4-2. Axial and equatorial geometries of the phenyl ring.

Fries and Portoghese (38) suggested that the analgesic receptor allowsnarcotic agents to interact with the phenyl ring, either axial or equatorial.Andrews and Lloyd (39) pointed out that such a proposal is not geometri-cally inconsistent with a common binding site (Fig. 4-2).

Belleau and co-workers (40) have hypothesized that the opiate receptoris flexible and can be specifically and divergently perturbed into a shapenegating the appearance of morphine-like effects. Specific conformationscan be structurally induced that are translated into analgesia whiledisallowing the pharmacological side effects of narcotics. The authorsinitially focused attention on the fact that naloxone (6) and naltrexone(19), both uniquely "clean" effectors, carry a unique polar substituentvicinal (at C-14) to the nitrogen atom. This, in turn, suggested that theintroduction of such a substituent at an equivalent position into potent but"unclean" morphinans might allow the synthesis of clean analgesics. Thecorresponding synthetic strategy was pursued (41), leading to the discov-ery of butorphanol (28), an analgesic with reduced narcotic side effects(42).

HO

28

Further investigations by Belleau and colleagues of the opiate receptorhave led to the clastic binding proposal (43). This proposal consists of two


p.arts: (a) a p.roductiv: effector-:rece~tor interaction requires a stereospe-cIfic lone pair (or N -H) onentatIon by the tertiary nitrogen at thereceptor site (44); (b) the binding event is accompanied by an oxidativeone-electron transfer from the lone pair of the nitrogen to the receptor (45)or by a proton t.ransfe~ fro~ .the corresponding salt to the receptor (46).

The hypothesIs of bIOactIvity dependence on the directionality of thenitrogen lone pair has been questioned by Shiotani et al. (47). Kolb (48),on the other hand, favorably evaluated the electron transfer proposal andextended the concept to include the formation of intermediate radical-anion-radical-cation pairs (49).

Tollenaere and Moereels (50) performed PCILO calculations to esti-mate t?e proton affinity (dEpA) of the basic nitrogen atom of morphine,~orphInan, benzomorphan, phenylpiperidine, and \fentanyl-type analge-SICS.Except for the phenylpiperidine, the dEpA values of these compoundsare ~340 kcaI/mole. These authors suggested that dEpA is a quantitativemeasure of the nature of chemical moieties in the vicinity of a basicnitrogen. They also presented examples that indicate an additive characterof dEpA.

Snyder et al. (51) have investigated oxidative one-electron transfermechanisms in a series of pyrrolidine- and piperidine-containing polycyclesthat are similar to morphine. They used the MM2 force field (52) with fullgeometry optimization to generate molecular structures. The MM2 cal-culations were followed by a set of approximate ab initio PRDDO (53)calculations using the molecular geometries determined by the MM2ca!culations. It may be noted that questions of computational accuracyanse when a molecular mechanics method is used to determine geometrieswhere .orientations of lone pair orbitals are a primary concern. Further,these workers did not optimize molecular geometry in the PRDDOcalculations s? that these workers had difficulty in achieving convergencefor PRDDO In some of the electronic configuration calculations.

Ease of ionization at the nitrogen atom of these compounds wasevaluat~d by com~aring relative nitrogen lone pair energies and bycomputIng energy difference between the neutral amine and radical-cationpai~s. ~bsence of a correlation between the ease of nitrogen lone pairIOnIZatIOnand analgesic activity for a set of compounds was interpreted tomean that oxidation clastic binding is not operative at the f-t opiatereceptor.

.The interaction of the quaternized amine group with an anionic receptor

site has also been considered using intermolecular modeling. Modelreceptor studies implicate a sulfate or phosphate moiety as a plausibleanionic receptor site (54). Loew et al. (55) have used a "supermolecule"approach employing the PCILO method (56) and fixed valence geometry

L


olecular mechanics force field calculations (57) to determine the inter-mlecular energy of complex formation between some N-substitutedmO .

A.

h Ibenzomorphans and model anionic receptor sItes. mmomum met yphosphate (AMP) and ammonium methyl sulfate (AMS) .were sel~~te~ as

del rece ptor sites. The calculated complex formatIon stablhzattonmod ffi

. . dergies with both anionic sites tend to follow the observe a mtles anen .potencies, as can be seen in Table 4-2. The three most potent antagonIstsare calculated to form the three most stable complexes with AMS and areamong the four most stable complexes with AMP. The two nearly pure

gonists have the smallest calculated interaction energies. Although there~ no measured binding constant for the 2-meth~lthiofuran compound, theweak antagonism does not correlate well wIth the calculated strongcomplex energy. .

Andrews and Lloyd (39) suggest that the search for a common analgesIcpharmacophore is actually hindered by the selection of ~orphine ~s. a

conformational standard. They reason that the conformatIOn of a ngldstructure like that of morphine may be far from optimal with respect tomaximizing analgesic potency. A more rational, if more diffi~ult,approach, from their point of view, would be to use newer, m?re flexible,and more potent analogs to deduce the common stereochemIcal compo-nents of analgesic activity. .

Andrews and Lloyd (39) pointed out that the presence of an aromatIcring and a nitrogen atom in most central nervous system (CNS) drugs haslong been recognized. However, these workers. note~ that molecu.larsuperposition studies of the crystal structur~s ?f elg~t dlvers~ CNS-actIngdrugs [chlorpromazine (antipsychotic), Imlpra~mne (anttdep~essant~,amphetamine (stimulant), LSD (hallucinogen),. dlphenylhy~antoIn (antI-convulsant), diazepam (anxiolytic), phenobarbItal (hypnotIc), and .mor-phine (analgesic)] indicate that the rin~s .and nitrog.ens,. respectIvely,occupy equivalent spatial locations. This IS Illustrated In FIg. 4-3. Theseauthors speculated about the possibility of a common CNS pharm~-cophore, of which the original analgesic model of Beckett and Casy (36) ISa specialized subset. .'

Loew and co-workers (58,59) carried out molecular orbItal calculatlO~s,including PCILO calculations (56), on a series of mix.ed agonist-anta?omstN-substituted rigid opiates. Two distinct conformatIOns correspondmg totwo different induced receptor site conformations are postulated. The twoconformations are shown in Fig. 4-4. Using this hypothesis, Loew et al.(59) suggested the synthesis of a series of morphine analogs predicted tohave a range of agonist-antagonist potency ratios. Some of these .c~m-pounds were synthesized and found to be active in preliminary prechOlcaltests (60).

N-R ANT" Kc x 109 c - AEpCILOd- AEEMPd

-ApCILOd -AEEMpdMethylcyclopropane 3.0 0.8 8.2 5.2 8.0 3.22-Methylfuran 0.66 2.5 6.8 5.5 2.1 4.23-Methylfuran O.66b 3.0 7.2 5.2 2.8 4.0Propene 0.22 6.2 3.8 1.0 2.9

_JEthylbenzene 0.03 10.0 7.3' 4.9' 1.8' 3.8'

co2-Methylthiofuran 0.024 9.1 4.1 1.4 3.82,3-Dimethylfuran 0.0 4.9 5.2 2.1 3.6Propane

3.1 -.f -.f -.f

0'::1.., 0.."3 ~.~.

~g .,r'I>......, .

~~:!1~...., (")

~o;-~ CO ....(JQQ 00

::s "0g f]....,g,::s-n>

..,

0' <J>0

<=::s

~"00'

'" '"..,3 ::s"0n>

~.n> ..,.., (JQ

'<o'c;: OJ::s---~a~3(JQ

:J:'"

..,-J 5' 0

0<;'-D3'

c:~"0

(")c: .., to

c..3 a

<'::>

;" 0'~::>:I: <J>'"

B :I:'"

..,(JQ C;;

(')'<..,

Z. <J>"0 5' V>..,

0,0 ::>~::; OJ<= 0"

5'c...., (JQ-. "0

e:::> ::s-(JQ -.::>

<=0;- '" (JQ..~::s

:§:0;(JQ

0'a::I~! ;"::><> n>..,0 (JQ

:;' ':'-

Table 4-2

Antagonist Potency and Binding Affinity of Benzomorphans with VaryingN-Substituents and Their Energies of Interactionwith Model Anionic Receptor Sites

a Antagonism relative to nalorphine = 1 in guinea pig ileum.h The 3-methylfurfuryl and 2-methylfurfuryl benzomorphans are equally potent antagonists in mice and monkeys, Noguinea pig ileum data exist for the 3-methyl analog.

C Stereospecific binding constants Ke.d -AE =units of energy in kilocalories per mole.'Calculated for be nzene.fNot calculated.

,.

Table 4-3

Net Atomic Charges and Bond Polarities inMorphine Protonated and Base Forms.

A, Nitrogen group atomic charges (a,u,)

Base Protonated

Atom PCILO INDO PCILO INDO

NI3 -0,13 -0.22 +0,07 +0,06C. +0,11 +0.14 +0,10 +0.12CI6 +0,09 +0.16 +0.09 +0,14CM +0.06 +0.16 +0,05 +0.12H... -0,03 ,,;,,0,04 +0,01 +0.00HI6 -0.02 -0,03 +0,03 +0.01HI6 -0.02 -0,05 +0,05 +0,02HM -0,01 -0,03 +0,05 +0.02HM 0,0 -0,03 +0.06 +0.04HM 0.0 -0.04 +0,05 +0,04HN +0.16 +0,15

IA +0.05 +0,02 +0,72 +0.72

B, N bond polarities (number of electrons in thebonding atomic orbitals of each atom)

II Molecular Modeling and OSAR Studies

Table 4-3 (com.)

C. Piperidine ridge atomic charges (a.u,)

Base Protonated

Atom PCILO INDO PCILO INDO

CIS 0,0 +0,04 -0,02 +0,03CI6 +0,09 +0,16 +0.09 +0.14HIs 0,0 -0,02 +0.02 0,00HIs 0.0 -0.02 +0,04 +0.02HI6 -0.02 -0.03 +0,03 +0,02HI6 -0.02 -0,03 +0,05 +0,02

D. Benzene and ring C atomic charges (a.u.)

Base Protonatedo Ringatom PCILO INDO PCILO INDO

CI -0.03 +0.01 -0,03 +0,03~-0,14 -0,03 -0.13 -0,02

C3 +0.16 +0,18 +0,17 +0,19C. +0,07 +0,13 +0.07 +0.14CI2 -0,07 -0,02 -0.09 -0,03CII +0.06 +0,02 +0.06 +0,00

C6 +0.13 +0.20 +0,13 +0,20C7 -0,03 -0,03 -0,01 -0.0CR 0.0 0,0 0,0 0.0C1. +0,02 +0.03 +0,01 +0,04CI3 +0.03 +0.03 +0.02 +0,02Cs +0,10 +0,17 +0.11 +0.18


The atomic charge densities and bond polarities were computed for boththe protonated and free base forms of morphine as part of these studies(58). These physicochemical properties are reported in Table 4-3 forgeneral reference. The calculated electrostatic potential patterns (61) ofmorphine derivatives were also generated for purposes of comparision andopiate receptor mapping. The electrostatic potential pattern of morphinein the plane of the benzene ring is shown in Fig. 4-5. A hydroxyl group wasused as the field probe to generate this figure. The atom numbering code isthe same as in Table 4-3.

Figure 4-5 indicates that the entire molecule is surrounded by a highlyrepulsive potential, which is typical of morphine-like molecules, andrepresents an "excluded region" analogous to a van der Waals radius. Thehighly positive potential attenuates at varying radial rates to zero fordifferent parts of the molecule. There are regions of negative potential of

Base Protonated

N-CII

N-C"N-CMN-H

1.06-0.941.06-0,941.05-0,94

1.29-0.731.26-0.751.22-0.781.25-0,84

181

E, 0 bond polarities (as in Part B)

Base Protonated

arC.OF-CSOrC306-C6

1.14-0,901,14-0.881.12-0,901.13-0.89

1.12-0.901.12-0,891.10-0.921.1 1-0.91.From ref. 58.

various extents and depths within the overall repulsive (+) potential regiongenerated by the molecule. It is these negative potential regions, togetherwith the large positive potential around the nitrogen cationic head, thatappear to constitute the major receptor-sensitive features of the rigidopiates.


~40

100

C,J<c.-I

100)

'0 -40

Fig. 4-5. Calculated electrostatic potential pattern of morphine in the plane of thebenzene ring.

Kaufman et al. (62-64) have used molecular potential contour maps,generated using a pseudo ab initio quantum chemical calculation (65,66),to differentiate between narcotic agonists and antagonists. In particular,eseroline (29) has been compared to morphine to explain opiate analgesicactivity (67). The potential fields about the pharmacophorically significantnitrogen atoms of eseroline and morphine are nearly identical. However,there are significant differences between the fields in the phenolic region aswell as other groups in these two molecules. Kaufman et al. have alsoemployed quantum chemical calculations to postulate the respectivemolecular requisites for interaction with 1-', 0, K, 0', and other opiatereceptors (67).

Conformational analyses of a series of oripavine derivatives (30) usingthe PClLO method (56) were carried out by Loew and Berkowitz (68) toidentify a structural basis for differences in agonist potency between

o

?H


:RI

C'~R2

"\OH

30

diastereoisomers of carbinol substituents at C-7. Low-energy conformersof the carbinol substituents are found with and without hydrogen bonding'to the C-6 methoxyl group. The relative energies of these conformersdepend on the R, and Rz groups as well as the diastereoisomerism of thealcohol. The authors suggested that the interaction of specific conforma-tions of C-19 carbinols and a lipophilic receptor site is critical to agonistpotency. However, no SAR applicable for molecular design can beextracted from this study.

Verlinde et al. (69) explored the role of the extra oxygen, common tomost benzomorphans with opioid K properties, on the net charges, bondpolarities, and proton affinities using the PClLO method (56). Net atomiccharges and bond polarities in the nitrogen region are very similar to thosecomputed by Loew and Berkowitz (59) for some morphine-like opiatenarcotics. Bond polarities and proton affinities were found to vary fromcompound to compound. However, no correlation with any measure ofanalgesic activity could be identified. This may be due in part to the factthat the calculations were carried out directly on crystal structures withoutdoing any geometry optimization.

A quantum mechanical model for the interaction of narcotic analgesicswith receptors was constructed by Gomez-Jeria and Peradejordi (70). Thedissociation constant was computed as a function of the net charge anddelocalizability of the drug. The calculated dissociation constant fit theobserved constant at the 98% confidence level.

B. QSAR Studies

Lien et al. (71) formulated a set of QSAR relationships for narcoticanalgesic agents using classical linear free energy descriptors. Mager (72)has applied pattern recognition methods to discriminate among morphino-mimetic opioids. Fries and Bertelli (73) have carried out a Hansch analysisfor a series of l-phenyl-3-aminotetralins and found the I-phenyl substituent

Substance

1 Elorphine; Elph( -)2 Fenlanyl: Fent( -)

3 Hydromorphnne; (Mph) (-),des ~7'= 011

4 Morphine: Mph( -)5 Dihydromorphine;

Mph(-), des ~,6 2(2-Furyl)elhyllevorpha-

nol; Lev( -), R]:CH2CHrfuryi

7 Normorphine; Mph( - ).R]=H

8 Levorphanol; Lev( - )

R,=CH39 Ketobemidonc; Ketb( -)

10 Methadone; Med(R)

A, j(x'j= 1) MSD

+0.22 1-30 5-0.82 4-6,9,13-18,20-21, 8

29-37, 43-46-1.09 1-20,30 8

-1.31 1-20,30 8- 1.38 1-20. 30 8

-1.38 1-14,16-19,30-36 8


is critical to the drug-receptor interaction. However, the conformation ofthe phenyl ring was not found to be decisive in specifying opiate activity.

Simon et al. (74) have attempted to map the analgesic receptor using thesteric mapping procedure [the minimum steric difference (MSD) approach]devised specifically for steric fit effects. A relationship was establishedbetween the analgesic activity after intravenous and intraventricularadministration, respectively, and the hydrophobicity of the molecule. Thereceptor model obtained by the MSD method agrees with Casy's model ofa goblet-shaped receptor site (37). However, the MSD model also predictsa side "lid" interacting with the extra ethylenic moiety of the etorphinecompound. A QSAR was derived from the following MSD-based analysis:

A, ~ 3.08- 0.55MSD

n~1I R~0.93

AI is the measured intraventricular analgesic activity and MSD is themeasure of steric fit (75). The numerical values for AI and MSD are givenin Table 4-4. There is considerable difficulty in understanding how both the

Table 4-4

Stereochemical Description and Correlations, Reduced Seriesa

II Pethidine; Peth(-).R]=Me,R2= R3 =H

-1.71 1-20 9

-2.18 1-14,16-19,30 10

-2.31 1-6,9. 11-14, 16-2029,30,47

1-6,9,11-14, 16, 1720, 29, 30, 47, 53,71-76

9

-2.78 II

-3.09 1-6,9,11-14,16-18,20.29,30,47

10

a From ref. 74.

.

References 185

MSD descriptors and biological activity measures are derived in this study.Also, the relationship between lipophilicity and MSD is not discussed,

In general, the QSAR studies on the morphine family are not as useful inrationalizing experimental observations or serving as a base in designingnew compounds as the molecular modeling efforts.

References

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(1982).10. I. L. Karle, Acta Crystallogr., Sect. B B3O, 1682 (1974).11. R. L. Sime, R. Forehand, and R. J. Sime, Acta Crystallogr. Sect. B B31, 2326

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(1973).14. K. Sasvari, K. Simon, R. Bognar, and S. Makleit, Acta Crystallagr., Sect. B B3O, 634

(1974).15. A. Kalman, Z. Jgnath, K. Simon, R. Bognar, and S. Makleit, Acta Crystallogr., Sect. B

B32, 2667 (1976).

16. L. Gylbert and D. Carlstrom, Acta Crystallogr., Sect. B B33, 2833 (1977).17. R. J. Sime, M. Dobler, and R. L. Sime, Acta Crystallogr., Sect. B 832, 809 (1976).18. J. H. van der Hende and N. R. Nelson, I. Am. Chern. Soc. 89, 2901 (1967).19. A. A. Liebman, D. H. Malarek, J. F. Blount, N. R. Nelson, and C. M. Delaney, I. Org.

Chern. 43, 737 (1978).20. H. van Koningsveld, T. S. Lie, and L. Maat, Acta Crystal/ogr., Sect. C C40, 313 (1984).21. R. Rull, Bull. Soc. Chirn. h p. 586 (1963).

22. S. Okuda, S. Yamaguchi, Y. Kawazoe, and K. Tsuda, Chern. Pharrn. Bull. 12, 104(1964).

23. W. Geiger and H. Wollweber, EUr. J. Med. Chern. 17, 207 (1982).24. H. Kugita, M. Takeda, and H. Inoue, Terrahedron 25, 1851 (1969).25. W. Fulmor, J. E. Lancaster, G. O. Morton, J. J. Brown, C. F. Howell, C. T. Nora, and

R. A. Hardy, Jr., J. Arn. Chern. Soc. 89, 3322 (1967).26. G. A. Brine, D. Prakash, C. K. Hart, D. J. Katchmar, C. G. Moreland, and F. 1.

Carroll, J. 0'8. Chern. 41, 3445 (1976).27. A. E. Jacobson, H. J. C. Yeh, and L. J. Sargent, Org. Magn. Reson. 4, 875 (1972).


28. H. J. C. Yeh, R. S. Wilson, W. A. Klee, and A. E. Jacobson. J. Pharm. Sci. 65,902(1976).

29. J. A. Glasel, Biochem. Biophys. Res. Commun. 102, 703 (1981).30. Y. Terui, K. Tori, S. Maeda. and Y. K. Sawa, Tetrahedron Let!. p. 2853 (1975).31. C. J. Kelley, R. C. Harruff, and M. Carmack, J. Org. Chern. 41, 449 (1976).32. F. I. Carroll, C. G. Moreland, G. A. Brine, and J. A. Kepler, J. Org. Chern. 41,996

(1976).33. J. G. Hexem, M. H. Frey, and S. J. Opella, J. Am. Chern. Soc. 105, 5717 (1983).34. E. Kutter, A. Herz, H..J. Teschemacher, and R. Hess, J. Med. Chern. 13,801 (1970).35. J. J. Kaufman, N. M. Serna, and W. S. Koski. J. Med. Chern. 18, 647 (1975).36. A. H. Beckett and A. F. Casy, J. Pharm. Pharmacal. 6, 986 (1954).37. A. F. Casy, Prog. Drug Res. 22, 149 (1978).38. D. S. Fries and P. S. Portoghcse, J. Med. Chern. 19, 1155 (1976).39. P. R. Andrews and E. J. Lloyd, Med. Res. Rev. 2, 355 (1982).40. B. Belleau, "Chemical Regulation of Biological Mechanisms," p. 201. Academic Press,

New York, 1981.41. I. Monkovic, H. Wong, A. W. Piccio, Y. G. Perron. I. J. Pachter, and B. Belleau, Can.

J. Chern. 53, 3094 (1975).42. F. S. Caruso, A. W. Piccio, H. Madissoo, R. D. Smyth, and I. J. Pachter, in "Pharmaco-

logical and Biochemical Properties of Drug Substances" (M. E. Goldberg, ed.), Vol. 2,p. 19. American Pharmaceutical Association-Academy of Pharmaceutical Sciences,Washington, D.C., 1979.

43. "Clastic" comes from the word "Klatos," which is Greek for "broken." In biology,"clastic" is used to describe a division into parts.

44. B. Belleau, T. Conway, F. R. Ahmed, and A. D. Hardy, J. Med. Chern. 17,907 (1974).45. B. Belleau and P. Morgan, J. Med. Chern. 17, 908 (1974).46. B. Belleau, U. Gulini, B. Gour-Salin, R. Camicioli, S. Lemaire, and F. Jolicoeur,

"Proceedings of the Second Camerino Symposium on Recent Advances in ReceptorChemistry," pp. 1-14 Elsevier/North.Holland Biomedical Press, Amsterdam, 1984.

47. S. Shiotani, T. Kametani, Y. Jitaka, and A. Itai, J. Med. Chern. 21, 153 (1978); S.Shiotani. J. Med. Chern. 21, 1105 (1978).

48. V. M. Kolb, J. Pharrn. Sci. 73, 715 (1984).49. R. B. Silverman, S. J. Hoffman, and W. B. Catus III, J. Am. Chern. Soc. 102, 7126

(1980); T. Shono, T. Toda, and N. Oshino,~. Am. Chern. Soc. 104,2639 (1982).50. J. P. Tollenaere and H. Moereels, Eur. J. Med. Chern. 15, 337 (1980).51. J. P. Snyder, T. A. Halgren, and V. M. Kolb, J. Med. Chern., in press.52. N. L. Allinger, J. Am. Chern. Sac. 99, 8127 (1977).53. T. A. Halgren and W. N. Lipscomb, J. Chern. Phys. 58, 1569 (1973).54. H. H. Loh, T. M. Cho, Y. C. Wu, and E. L. Way, Life Sci. 14, 2233 (1974).55. G. Loew, S. Burt, P. Nomura, and R. Macelroy, in "Computer Assisted Drug Design"

(E. C. Olsen and R. E. Christoffersen, eds.), p.243. American Chemical Society,Washington, D.C., 1979.

56. J. L. Coubeils, P. Courriere, and B. Pullman, C. R. Acad. Sci. Paris 272,1813 (1971).57. A. J. Hopfinger, "Conformational Properties of Macromolecules." Academic Press,

New York, 1973.58. G. H. Loew, D. Berkowitz, H. Weinstein, and S. Srebrenik, in "Molecular and

Quantum Pharmacology" (E. D. Bergmann and B. Pullman, eds.), p.355. Reidel,Dordrecht-Holland, 1974.

59. G. H. Loew and D. S. Berkowitz, J. Med. Chern. 18, 656 (1975).60. J. J, DeGraw, J. A. Lawson, J. L. Crase, H. L. Johnson, M. Ellis, E. T. Uyeno, G. H.

Loew, and D. S. Berkowitz, J. Med. Chern. 21, 415 (1978).

References 187

61. P. Politzer and D. G. Truhlar, eds., "Chemical Applications of Atomic and MolecularElectrostatic Potentials." Plenum, New York, 1981.

62. J. J. Kaufman, Int. J. Quantum Chern. 16, 221 (1979).63. J. J. Kaufman, NIDA Res. Monogr. No. 22, p. 250 (1978).64. J. J. Kaufman, P. C. Hariharan, F. L. Tobin, and C. Petrongolo, in "Chemical

Applications of Atomic and Molecular Electrostatic Potentials" (P. Politzer and D. G.Truhlar, eds.). Plenum, New York, 1981.

65. H. E. Popkie, W. S. Koski, and J. J. Kaufman, J. Arn. Chern. Soc. 98, 1342 (1976).66. H. E. Popkie and J. J. Kaufman, Int. J. Quantum Chern. 10, 569 (1976).67. J. J. Kaufman, in "Advances in Endogenous and Exogenous Opioids, Proceedings of

12th International Narcotics Research Conference" (T. Hiroshi and E. J. Simon, eds.),p. 417. Kodansha, Tokyo, 1981.

68. G. H. Locw and D. S. Berkowitz, J. Med. Chern. 22, 603 (1979).69. C. L. Verlinde, N. M. Blaton, C. J. De Ranter, and O. M. Peeters, J. Med. Chern., in

press.70. J. S. Gomez-Jeria and F. Peradejordi, Bal. Soc. Chilo Quim. 27, 145 (1982).71. E. J. Lien, G. L. Tong, D. B. Srulevitch, and C. Dias, NIDA Res. Monog. No. 22,

p. 186 (1978).72. P. P. Mager, Act. Nerv. Super. 23, 136 (1981).73. D. S. Fries and D. J. Bertelli, J. Med. Chern. 25, 216 (1982).74. Z. Simon, N. Dragomir, and M. G. Plauchithiu, Rev. Rourn. Biochirn. 18,139 (1981).75. Z. Simon, I. Badilescu, an? T. Racovitan, J. Theor. BioI. 66,485 (1977).

Table S.I

Plant Sources of Morphinan Alkaloids

Plant Reference Plant Reference

Cassytha 3 Nemuaron 9Cocculus 4 Ocotea 10Colchicum 5 Papaver 11Corydalis 3 Rhiziocarpa 12Croton 3 Sinomenium 13Fumaria 6 Stephania 14Glaucium 7 Thalictrum 15Meconopsis 8 Triclisia 16

II Naturally Occurring Morphinans 189

5. occurrence of these types of molecules in nature, partial and totalsyntheses of the tetracyclic structure, and structure-activity relationships.Because of the close similarity of the morphinans and morphine, structure-activity relationships for analgesic activity are presented in a format andapproach similar to that used for morphine. For the morphinans, thosesimilar positions substituted in morphine are considered as a group, whilethe nonfunctionalized positions are a second group.

The Morphinans

I. Introduction . . . . . . . . . 188II. NaturallyOccurringMorphinans. . . . . . . . . . . 189

III. Conversion of Morphine and Its Analogs to Morphinans . 190IV. The Total Synthesis of Morphinans . 193

A. GreweCyclization . . . . . . . . . . . . 193B. The Total Synthesis of 14-Hydroxymorphinans 199C. OxidativeCouplingto Morphinandienones. 201D. Electrochemical Oxidations . . . . . . . . . 204

V. Structure-Activity Relationships of the Morphinans . . . 206A. Alteration of Existing Functional Groups and Structures. . . . . . . 207B. The Effect of Substituents in Nonfunctionalized Positions on Morphinan

Analgesia. 220C. Ring Additions, Contractions, Enlargements, and Movements in the.

Morphinans . . .. 230D. Movement of the Nitrogen within the Molecular Framework and

Heteroatom Insertion. .. .. 236VI. The Chemical Anatomy of the Morphinans 242

References 243

II. Naturally Occurring Morphinans

1. Introduction

The first isolation of a morphinan from a natural source occurred almost20 years after the description of the synthetic material. The naturallyoccurring compounds contain a dienone grouping or a reduced version ofit. The first alkaloid of this group identified was salutaridine (1), and it wasisolated from Croton sa/utaris (1). Salutaridine was probably identical tofloripavine, reported by Russian workers in 1935 (2). . .

Interestingly, 1 is an intermediate in the bIOsynthesIs of morphmefrom tyrosine and was ultimately isolated from opium. The morphinandi-enone alkaloids have been isolated from a wide variety of plant genera(Table 5-1).

The diversity of structure in the morphinan alkaloids parallels, in manyrespects, the structure-activity relationships of the .mo~hine-bas~danalgesics. Since salutaridine is an intermediate in morphme bIOsynthesIs,it has the same absolute configuration as morphine. However, its enan-tiomer, sinoacutine (2), has been isolated from Sinomenium acutum (17).This occurrence was taken advantage of when sinomenine (3) was con-verted into (+ )-morphine, the unnatural enantiomer (18). The presence ofa 14-hydroxyl group in morphine derivatives has been underscored in

For many years, investigations on the modification or separation ofmorphine's biological properties centered on the modification of existingnatural products. A complementary approach was the simplification of thebasic molecule itself. One of the simpler conversions, on paper at least,was cleavage of the dihydrofuran ring to provide the tetracyclic nucleus,ultimately termed the morphinans. Although several other simpler deriva-tives of the rigid opiates had been prepared prior to the total synthesis ofthe first morphinan, the analgesic activity of these tetracyclic derivativesled to intensive investigation of these compounds, particularly in the mixedagonist-antagonist and antagonist series. This chapter discusses the

"

188

190

1 (salutaridine)

3 (sinornenine)

5 (nudarine)

5 The Morphinans

2 (sinoacutineJ

4 (tridictophylline)

6 (dihydronudarine)

Chapter 3. This substituent is usually incorporated using thebaine in-termedIates. !n the morphinan series~ a naturally occurring 14i3-hydroxydenvatlve, tnd~ctophylline (4), with the correct enantiomeric configura-tIOn, has been Isolated (16). Besides the structural features illustrated in~tructur~s 1 t~ 4, a substantial variety of morphinan alkaloids have beenIsolated In whIch the ketone has been reduced or a double bond saturatedfor example, nudarine (5) and dihydronudarine (6) (19,20). '

III. Conversion of Morphine and Its Analogsto Morphinans

While many morphinans have been used in the synthesis of morphineand related alkaloids (cf. Chapter 3), the ready availability of largeamounts of morphIne, codeIne, and thebaine have made the reversal of

III Conversion of Morphine and Its Analogs to,Morphinans. 191

this process attractive. The formation of morphinans from morphine andcodeine, as well as a host of other alkaloid-derived derivatives, has beenobserved during the investigations of the structure and rearrangements ofthese opium alkaloids. The early work in this area, which is oftenconfusing, has been reviewed and summarized (21). While an exhaustivereview of cleavage methods will not be attempted, the more commonlyused or interesting methods will be indicated.

The majority of cleavage methods proceed from a 6-ketone. Forinstance, the generally used reagent for rupture of the dihydrofuran bridgeis zinc and ammonium chloride (22,23). Dihydrocodeinone (7) is rapidlycleaved to dihydrothebainone (8) by this method. A 1413-hydroxyl group,which is important for analgesia enhancement, usefully survives theseconditions (24). Reduction of 9 gives 10 in good yield. Other previouslyused methods included tin (25) and zinc or sodium analgams (26).

Interesting approaches are the decomposition of hydrocodeinone hydra-zone under Huang-Minion conditions to yield the morphinan olefin (II).

Zn

NH4Cl

7 8

Zn

9 10

11

192 5 The Morphinans

12 (thebaine)13

a.j

,au

b.1

14Scheme 5-1. Reagents: (a) Claisens alkali; (b) diazomethane.

An alternative method for preparing 8 from 7 is heating with ethylmercaptan and hydrochloric acid. The reaction mechanism proceedsthrough a phenoxide displacement by mercaptide to form the 5-ethylthio-morphinan, which can be isolated. The thioether is then displaced byadditional mercaptan to form 8 (27).

A novel way to form the morphinandienone alkaloid salutaridine (I)proceeds through 14-bromocodeinone (13), which is available from the-baine (12) in one step (Scheme 5-1). Heating 13 with alkali results in a

IV The Total Synthesis of Morphinans 193

series of addition eliminations to yield 14 as the only isolated product.Methylation of the acidic hydroxyl at C-6 produces salutaridine (I) in a fairoverall yield (28). A shorter, more efficient alternative is oxidation ofthebaine (12) with air in the presence of sodium bisulfite, whereby 14 isformed directly in excellent yield (29).

Cleavage of the dihydrofuran ring in thebaine (12) with retention of thedienol ether allows access to morphinan analogs of the extremely potentthebaine Diels-Alder adducts. Birch reduction of thebaine gives only theenol ether (IS) (30), which cannot be converted to the conjugated diene

~thebaine (12)~or c

15 16

Reagents: f (a) Na/NH3, (b) LAH, (c) KIN"]

(16) (31). Various hydride reductions of 12 to 16 have been described (32),but ultimately the reactions were found to be too carpricious and non-reproducible (30). A partial solution to the problem of the preparation of16 is the reduction of 12 with potassium in liquid ammonia, wherebyequimolar amounts of IS and 16 are formed and separated by crystalliza,tion (33).

IV. The Total Synthesis of Morphinans

A. GreweCyclization

Morphine can be considered both a phenanthrene and an isoquinolinederivative, and many of the early attempts at synthesis focused on thepreparation of hydrophenanthrene derivatives. A summary of the modelstudies has appeared (34). Cyclization of the acid (17) leads to twounexpected structures 18 and 19, the latter of which has striking similarityto the heterocyclic ring system of morphine (35). The structure of 19 andRobinson's hypothesis on the biogenetic formation of morphine (36) ledGrewe to publish his speculations on a biomimetic synthesis of morphine-like alkaloids from suitably reduced isoquinolines (37). In using thebiomimetic approach, the reduced isoquinoline (20), which carries the


+

H3P04

17 18 19

20

j

20

22 21

requisite phenethyl-cyclohexene grouping necessary for phenanthreneformation, was chosen. Using the acidic conditions that were successful inthe alicyclic syntheses, cyclization of 20 should yield the desired tetracyclicmorphinan ring system (21). The alternative cyclization to form thehydroaporphine (22) could also occur. Since this approach occurs througha cyclodehydration, it is biomimetic in a formal sense only, since morphineis formed biosynthetically through one-electron transfer oxidations (ef.Chapter I).

The realization of this hypothesis is illustrated in Scheme 5-2. ModifiedKnoevenagel condensation of a-carbethoxycyclohexanone yields the un-

IV The Total Synthesis of Morphinaos 195

23

c d

fl,. <ph or",,->

0<'7"1, loy;.t,

e

OH

f

25

20

h

21

1

(~j.."l>,+;

~y1Y"j'''''lea,,), . OV& P

4.el.(~( ~e 0,Cp.~c~J..1. ~J.;

9 <"'r""iI;<j

C1

th\, el'\~"""/~ n<: C",,",+-0.1'7 &. cia

f-hrl., , CC'l'I~,;<:

Hy..l,,'~ R~j,"{+7

f;;:;,fr.J5: (",.4.117.1.

Scheme 5-2. The Grewe morphinan synthesk Reagents: (a) ethyl cyanoacetate; (~)saponification and decarboxylation; (c) ammonia; (d) phosphorus oxychloride; (e), cat~lytlc

hydrogenation; (f) methyl iodide; (g) benzyl magnesium chloride; (h) phosphonc aCid.


+

HO

27 (R1""CH3,Ri"H)

30 (R1 =CHO, R2"'CH3)

28 (3%)

31 (85%)

Scheme 5-3.

29 (37%)

saturated ester (24), which is converted to the heterocycle, 5,6,7,8-tetrahydroisoquinoline (25). After formation of the methyl imminium saltof 25, grignard addition to the activated double bond yields the I-benzyl-hydroisoquinoline (26). This can be reduced by catalytic hydrogenation tothe penultimate product (20). Today, this enamine reduction is usuallydone by complex hydride reduction. Treatment of the isoquinoline (20)with phosphoric acid then yields the parent compound of the morphinanseries (21) (38,39). A great deal of synthetic effort is required to prepare25, a crucial intermediate in the synthesis. Although early work indicatedthat it was not possible to prepare 25 by catalytic hydrogenation ofisoquinoline, reduction over platinum in acidic methanol yields 25 in veryhigh yield (40). This cyclization to morphinans has become a namereaction in organic synthesis: the Grewe cyclization (41).

Synthetic improvements have included the use of the formamide insteadof the N-methylamino in the isoquinoline (42). The use of this protectinggroup allows the cyclization reaction to proceed at a rate 400 times fasterthan that of the N-methyl. Cyclization catalysts other than phosphoric acidhave included phosphoric and sulfuric acids (42), hydrochloric acid (43),hydrobromic acid (44). trifluoromethane sulfonic acid, and trifluoro-methane sulfonic acid containing ammonium hydrogen bifluoride (45).The use of various protecting groups or substituents, as well as the prob-lems inherent in unsymmetrical substitution on the benzyl radical, areillustrated in Scheme 5-3. Cyclization of 27 with either phosphoric orhydrochloric acid yields a mixture of two products, 28 and 29, in a ratio of1:10 (46,47). The minor isomer (28) possesses the correct regiochemistryfor conversion to codeine. With the introduction of a methyl group and theuse of a formyl group on the nitrogen, cyclization of 30 with sulfuric acidproceeds more rapidly and in much higher yield to produce 31 with the

I

~l

IV The Total Synthesis of Morphinans t97

correct regiochemistry (48). However, the I-methyl group in 31 is notremovable. This problem has been solved by the use of the bromo (30)(R1 =CHO, R2 = Br) or hydroxy derivative (30) (R1 = CHO, R2 = OH)where the blocking group is ultimately removed by hydrogenation (cf.Schemes 3-4 and 3-5) (45,49).

After the pioneering discoveries of Grewe, and as interest increased inthe morphinans, the need for a commercial synthesis of this ring systembecame apparent. In addition, a common intermediate was necessary. Thisintermediate had to avoid the demethylation step that was inherent in theoriginal synthesis to allow access to a wide variety of derivatives. Theapproach chosen was to use a cyclohexenylethylamine in place of thetetrahydroisoquinoline and is outlined in Scheme 5-4 (50). The crucialstep in the synthesis is the extension of the Bischler-Napieralski reactionto appropriately placed, isolated double bonds. Previously, this cy-clodehydration had been used only with aromatic rings. The requisitecyclohexenylethylamine (33) is readily prepared from cyclohexanone (32),and the amide (34) is obtained by heating 33 with a phenylacetic acid.After selective reduction and demethylation of the phenolic ether, thesecondary amine (35) can be readily alkylated with a wide variety ofsubstituents, thus meeting the second condition for a general intermediate.Cyclization to the morphinan then occurs according to standard Greweconditions (50-53). To obtain the pure enantiomers, resolution can beeffected either at the isoquinoline (36) (R = CH3) (54) or the morphinan(37) (R = CH3) stage (55). However, on a commercial scale, the isoquino-line (35) is readily resolved using tartaric acid (56).

The morphinans produced by the Grewe reaction under the conditionslisted above lead to rings BC cis-fused. When the BC ring junction istrans-fused, the resultant tetracycle is termed an isomorphinan. Access tothe isomorphinan system has been more difficult than access to themorphinan one. It was first prepared, in a lengthy sequence, during Gate'ssynthesis of morphine (ct. Scheme 3-1) (57). Subsequently, it was synthe-sized, again in a difficult sequence, from thebaine (12) (58). In thebenzomorphan series, use of aluminum chloride for the catalyst givessignificant amounts of the trans isomer (59). Use of this reagent with 38gives substantial amounts of the isomorphinan (39), which can be sepa-rated from the morphinan by differential rates of quarternization withmethyl iodide (60).

While the Grewe method for the synthesis of morphinans generally givesgood yields, by-products, which can occasionally be troublesome, are alsoformed. One by-product consistently formed in 10-15% yield in thecyclization of 38 is the aporphine derivative (40) (61). Compound 40probably arises through double bond migration in 38 and subsequent

HO

OCNH

40d e,f H

~~-CH3

OCH3 H334

41 42 43

9cyclization and ether hydrolysis. The Grewe cyclodehydration of 41 hasfailed to yield any morphinan but is converted into the cyclic ether (42),which slowly rearranges to the aporphine (43). The stereochemistry of 43and the structures of 42 and 43 have been elucidated by X-ray analysis(62). The other usual accompanying by-product of morphinan synthesis is

OH H the isomorphinan formed in 3-5% yield (63).35 36

198 5 The Morphinans IV The Total Synthesis of Morphinans 199

6 +a

AiCl)

32

38 39

c5 b~

c

33

h--7

B. The Total Synthesis of 14.Hydroxymorphinans

The presence of a 14,B-hydroxyl group in the morphine series enhancesthe analgesic potency of these molecules compared to that of the unsubsti-tuted parent. The introduction of this group into the morphinan seriesrepresents a synthetic challenge, since the Grewe reaction does not lenditself to the introduction of this functional group. The ultimately successfulmethod is illustrated in Scheme 5-5 (64). The readily available a-tetralone(44) is spiro-annulated (45) and then converted to the hydroxyamine (46).

37

S.c~eme 5-4. A commercial synthesis of the morphinan ring system. Reagents: (a)~yndlDe; (b) H2. Rane~ Co; (c) p.methoxyphenylacetic acid, heat; (d) phosphorus oxychlo-nde; (e) H2. Raney NI; (f) demethylation; (g) alkyl halide; (h) Grewe cyclization.

HO

l


a'>

b.c---+

HO

4645

d f

47 48

f,g,h

50 (H-H)

51 (R;COCF3)

j,c

53Scheme 5.5. Synthesis of 14-hydroxymorphinans. Reagents: (a) sodium hydroxide. 1,4-

dibromobutane; (b) acetonitrile, base; (c) lithium aluminum hydride; (d) hydrochloricaqueous; (e) bromine; (f) sodium bicarbonate; (g) 13S"C in DMF; (h) trifluoroaceticanhydride; (i) m-chloroperbenzoic acid; (j) sodium borohydride. .

Treatment with acid causes rearrangement and dehydration to the hyd-rophenanthrene derivative (47). The fourth bridging ring is introduced bystereospecific bromination from the a face of 47, whereby the intermediatebromonium ion is captured by the amine. The resulting product (48) hasthe ring system characteristic of the hasubanane alkaloids, naturallyoccurring opium alkaloids. The free base of 48 forms the aziridine (49),which is isolable at low temperature. Heating (49) in the presence of weak

IV The Total Synthesis of Morphinans 20t

a

9H

b ,-co-O

e

CH]O

Scheme 5-6. Reagents: (a) m-chloroperhenzoic acid; (b) 64% sulfuric acid in 2-butanone;(c) LAH; (e) phosphoric acid.

base causes elimination to morphinan (SO) with 8(14)-unsaturation. Afteracylation of SO, the amide (51) is selectively epoxidized on the {3face (52),which is reductively hydrolyzed to the 14{3-hydroxymorphinan (53)(64,65). This general reaction has served for the synthesis of many14{3-hydroxy compounds, as well as another approach to isomorphinansvia 47 (66a).

The Grewe cyclization has been successfully applied in the preparationof 14-hydroxymorphinans (Scheme 5-6). Epoxidation of the amide inScheme 5-6 yields a mixture of diasteromers that is converted into the transdiol in 75% yield. After reduction of the amide to the amine andcomplexation with borane, the diol is smoothly cyclized with phosphoricacid to the 14-hydroxymorphinan in 65-70% yield (66b).

C. Oxidative Coupling to Morphinandienones

The oxidative coupling of l-benzylisoquinolines to form the morphinan-dienone ring system originated in experiments designed to mimic the

54 55

CH3l::,

CH30

CH3 CH30

202

Cu

5 The Morphinans

OR

56 (R=CH3)

60 (R-CH2C6H5)

57 (R=CH3) (1%)

61 (R=CI/2C6H5)

62 (R=H) (2%)

+

RO

58 (1%)

64

59 (R=CH3) (1.4%)

63 (R=CH2C6H5) (8.4%)

OCH3

65 (25%)

I!I

I

IIi

II

I

IV The Total Synthesis of Morphinans 203

biosynthesis of the morphine alkaloids (67). Two approaches have beentaken: (a) the use of the Pschorr reaction and (b) one-electron transferoxidizing agents. The Pschorr reaction (68) has, on the whole and with anoccasional exception, given very low yields. This reaction consists ofthedecomposition of a diazotized benzylisoquinoline (58) and has been usedprimarily to synthesize aporphines (55), although dienones can also beformed (69). The use of one-electron oxidizing agents, on the other hand,started with very low yields of morphinandienones, but as reagents haveimproved, this became a useful way of synthesizing these complex mole-cules.

The scope of the Pschorr method of producing the morphinan ringsystem can be illustrated with compounds 56, 60, and 64 (70). Decomposi-tion of the diazonium salt (56), which is readily prepared from the nitroderivative via the amine, yields approximately 1% each of the deaminationproduct laudanosine (57), the aporphine glaucine (58), and the morphinanO-methylflavinantine (59) (71). The cydization products 58 and 59 resultfrom the reaction of the electrophilic species produced in the diazoniumdecomposition with the starred positions in 56. When the trivial substitu-tion of a benzyl for a methbxyl methyl group is made in 56 to produce 60,the decomposition furnishes small amounts of the two deamination pro-ducts 61 and 62, but the morphinandienone (63) yield increases sixfold(72,73). When the position that leads to the aporphine type of structure(55) is blocked, the formation of the morphinandienone is enhanced, forexample, 64 to 65 (74). In general, the Pschorr approach to morphinan-dienones remains of academic interest only.

One-electron oxidizing agents have been extensively studied, mainly inan effort to mimic biosynthetic pathways. However, some of the reagentsthat have been developed provide the morphinan ring system in syntheti-cally useful yields. Initially, Barton studied the oxidation of reticuline (66)(R = CH3) to salutaridine (1) in order to provide chemical evidence for thebiochemical conversion of reticuline to salutaridine and eventually tomorphine (67). A wide range of oxidants was investigated, but 1 wasobtained in a maximum yield of 0.015%. Since then, extensive investiga-tions of the oxidation of 66 by a wide variety of inorganic oxidizing agentshave shown that the major morphinandienone product (67) is isomericwith I. Compound 67, pallidine, or its derivatives can now be prepared ingood yield, especially considering the degree of complexity and reactivityof the molecule formed (Table 5-2). The structure of the molecule beingoxidized may exert a profound effect on the yield of the resultantmorphinan. While the conversion of 66 to 67 with VOCl3 is very low, thesame reagent with the isoquinoline (68) yields the morphinan (69) in 34%yield (81).

104

Table 5-2

5 The Morphinans

Formation of Morphinandicnoncs Using One-Electron Oxidizing Agenrs

R

CH)CH3CH,COCF,COCF,CO,CH,CH,CHO

orCO,CH,CH,CHO

orCO,CH,CH,

66

Oxidant

MnOzsilica gel

K,Fe(CN),AgzCO.\-CeliteVOCI,VOF,TI(O,CCH,hTI(O,CCH,hPb(O,CCH,),

trichloroacetic acid

C,H,I(O,CCH,htrichloroacetic acid

VOC13

34%

68

[0)

Yield (%) Reference

4 75

0.90.50.38

1123

18-40

76777778797980

14-31 80

69

D. Electrochemical Oxidations

The important role played by phenolic coupling in morphine alkaloidbiosynthesis is described In Chapter 1. As previously discussed

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(Section IV,C), attempts to carry out these phenolic couplings in thelaboratory have been only partially successful due to the susceptibility ofthe products to further oxidation. As an alternative approach to the use ofinorganic oxidants, controlled potential electrochemical oxidations havebeen investigated. This electrochemical method ultimately led to thesynthesis of the morphinan ring system in virtually quantitative yield.Initial attempts to oxidize reticuline (66) (R = CH3) were unsuccessful.However, protection of amine nitrogen as a carbamate (66)(R = C02CH2CH3) and anodic oxidation resulted in the isolation of themorphinandienone (67) in 15.5% yield (82).

The major breakthrough occurred with the discovery that it was notnecessary and, indeed, was undesirable to have free phenolic groups in thebenzylisoquinoline. For example, the tetramethoxybenzylisoquinolinelaudanosine (57) could be electrochemically oxidized to the morphinan-dienone (59) in yields of up to 93% (Table 5-3), compared to 15% for thefree phenol (83). The conditions for the electrolysis appear to be critical,with the best being anodic oxidation at 1.0-1.2 volts in acetonitrile andfluoroboric acid. The regiochemistry of the cyclization is the same asthat for the inorganic oxidant, with oxygenation at the 2,3-positions ofthe morphinan molecule rather than at the 3,4-position characteristic ofthe majority of the morphine and morphinan-based alkaloids. A varietyof attempts to force the 3,4-oxygenation pattern has been uniformlyunsuccessful.

V. Structure-Activity Relationships ofthe Morphinans

When research into the analgesic properties of the morphinans becameimportant, extensive structure-activity relationship correlations in themorphine alkaloid series were already available. Since the morphinanswere similar to morphine, lacking only the ether bridge, the assumptionwas made that substitutions that were effective in the morphine seriescould be transferred directly to the morphinans. As a result, a great dealof the research interest in the morphinans has been in the substitution ofthe bridge nitrogen. As with morphine, the objective was to prepare eithermixed agonist-antagonists or pure antagonists that were analgesics withoutthe undesirable side effects of morphine. A major difference between thetwo series is that the morphinans are usually made by total synthesis,readily furnishing both enantiomers by resolution techniques and facilitat-ing biological differentiation. This has led to the discovery of potentantitussive agents that lack the usual opiate side effects.

'\

i

L

V Structure-Activity Relationships of the Morphinans 207

Table 5-4

Comparative Analgesic Effects of Morphinan Enantiomers

EnantiomericComposition

AnalgesicPotencyII'R

(=)(-)(+)(=)(-)(+)

H (racemorphan)H (levorphan)H (de'drorphan)CH) (racemethorphan)CH) (levomethorphan)CH] (dextromethorphan)

2-2.55

0.20.5

Q Morphine = 1, SC, in rats.

A. Alteration or Existing Functional Groups and Structures

I. Enantiomers One of the initial syntheses of the morphinan ringsystem was the preparation of the 3-phenol (37) (R = CH3) (90.). Thiscompound, racemorphan, is a potent analgesIc, bemg about two times asactive as morphine (Table 5-4) (91). In contrast to morphme, which exertsits analgesic action orally only in relatively high doses,. racemorphan ISactive in humans both orally and parenterally at eqUivalent doses of1-2 mg. Resolution of the racemic compound into its enantiomers demon-strated that the analgesic activity resided exclusively in the levorotatoryisomer levorphan (levorphanol). The dextrorotatory isomer (dextror-phan) was inactive as an analgesic. The side effects of levorphanol andracemorphan are similar to those of morphine (92). However, dextror-phan, although inactive as an analgesic, p~ssesses cough-suppressantproperties and is free from the side effects mherent 10 morphme andlevorphanol. As a general rule in the morphinan series, the de~trorota~oryisomers have antitussive properties. In common with the relative acllvltlesof morphine and codeine, racemethorphan (Table 5-4) has about 10% ofthe activity of racemorphan (91) and is more potent as an antitussive agent.Optical resolution again has demonstrated that the analgesIc effects reside 10the levo-isomer, levomethorphan. The potent antItussive effect resides. 10the dextro-isomer, dextromethorphan, which is free from the opIate side

Enantiomeric Other Analgesic Enantiomeric AnalgesicComposition R Substitution Potency" Composition R Potency. References

(-) CH, 8-10 (-) H (2t) 0.5 52,101(+) CH, Inactive at 32 mpk (-) HO (37) 5 92(-) CH, t:,' -7-8 (=) CH,CO, Strong 34,90(+) CH) t:,' 0.25 (=) CH,O Strong 34,52,90

(-)' CH,-<](=) CH,CH,O Strong 54,102a

Inactive" (=) CH,CH,CH,O Weak-inactive 34,102a

(=) CH,=CH,CH,O Weak-inactive 34,50Q

Relative to morphine= 1; tail flick test in rats. (=) C6:f{sCH2O Weak-inactive 34,50b Antagonist potency relative to nalorphine = 7. (-) C6HsO 0.5 102b

" Agonist activity is less than 1/300th that of cyc10rphan in the PSQwrithing test. a Relative to morphine = 1.

208 5 The Morphinans V Structure-Activity Relationships of the Morphinans209

Table 5.5 Table 5-6

The Effect of Substituents at C-3 on Morphinan AnalgesiaAnalgesic Activity of Isomorphinans

effects demonstrable in levomethorphan (93-95). Dextromethorphan iswIdely used as a cough suppressant. Similar separations of activities havebeen observed with a variety of N-substitutions (96).

2. Ring BC trans-Morphinans (Isomorphinans) A substantialamount of effort has gone into the synthesis of both trans-codeine andtrans:morphine where the usual cis-decalin stereochemistry at the BC ringJunctlO~ has been Inverted to the trans-decalin stereochemistry (97). TheanalgesIc potencIes of both trans-codeine and trans-morphine have bothbeen disappointing, bei~g 0.5 that of codeine and 0.1 that of morphine,respeclIvely. The work In the pentacyclic series has been based on data~btained originally in the morphinan series. Although the Grewe cycliza-lIon can be .modlfied to p~oduce substantial amounts of isomorphinans(60), the onglnal preparatIon of the isomorphinan ring system was anoutgrowth of the Gates total synthesis of morphine (57,58). The racemicmIxture was resolved using tartaric acid to furnish the pure enantiomers.As c?n be seen In Table 5-5, levo-enantiomers retain analgesic activity.The Isomorphlnan analog of levorphan (Table 5-4) is twice as potent aslevorphan and 10 tImes as potent an analgesic as morphine (98). Interes-tingly, the dextroisomorphinan containing unsaturation at C-6 apparentlyretains some Inherent analgesic potency. The isomorphinan analog ofcyclorphan (R = cyclopropylmethyl), a potent mixed agonist-antagonist,

is essentially without any analgesic potency (60,99). 11appears that in theagonist isomorphinan series, analgesic potency is increased over that ofthe equivalent morphinan. In the mixed agonist-antagonist series, theeffect is still unclear.

3. The Aromatic Ring and the Phenolic Function at C-3 The presenceof a phenolic 3-hydroxyl group and its ethers and esters in the morphinanshas been studied for its effect on analgesia as well as for ItS coughsuppression. On the whole, the structure-activity relationships follow theobservations made for the morphine alkaloids. For instance, the 3-hydroxyl group can be readily removed using the Musliner-Gates ~eagent(/00) to furnish the 3-deoxy compound (21), which has approxImatelyVlOth the potency of levorphan (37) (Table 5-6) (52,lOI). Acetylation ofthe 3-hydroxyl group yields a compound with equivalent analgesic effectsbut with a shortened duration of action (90). Formation of the methylether results in a reduction of analgesic activity (52,90), while longer chainethers rapidly cause the loss of analgesia. The allyl and propyl ethers areessentially inactive (50). The phenoxy ether is 0.5 times as potent ananalgesic as morphine, with a longer duration of action and decreasedphysical dependence liability (102b,c). The phenoxy ether may functIOn asa prodrug for levorphanol (37) (lOld).


The antitussive activity of the dextro-morphinan isomers approximatelyparallels the an~lgeslc potencies in the 3-ethers, with the methyl (dextro-methorphan) beIng the most potent. Antitussive activity decreases as chainlength mcreases (103,104). [nterestingly, a 3-methyl substituent, which isstencally more bulky than either a hydroxyl or a methox yl grou p d td h

..'

oes noecrease t e antItussIve activity (105).

[n the ~ripavine Diels-Alder adducts, it is not necessary to have an

~romatlc rmg present for analgesic activity to occur. This effect has beenm.vewgated t.n the morphinan series by Birch reduction. Reduction of 37wIth lithIUm 10 ammOnIa gIves the nonaromatic morphinan 3-ketone (71)after hydrolysIs of the enol ether (70). Similarly, the isomorphinan (72)gIves the BC-trans 3-ketomorphinan (74)' (106). Neither of these com-pound~ has demonstrated any analgesic activity in the rat tail flickassay, m~'catmg ~he necessity of an aromatic ring in the morphinan and~somorphman senes.

>

37 (BC-cis)

72 (BC-trans)

70

73

71

74

>

75 76

4. The 6-P~sition in the Morphinans The 6-ketone substituted mor-phmans are an mterestmg group of molecules because of their unexpected-

l


Table 5-7

Analgesic Potency of 6-Ketomorphinanswith Single A-Ring Substitutions

1

2

Substitution Pattern Analgesic ActivityU

None (76)3.0H (77)3.0CH, (78)1.OH (80)l-OCH, (82)2-0H (83)

2-0CH, (84)4-0H (75)4.02C:CH, (86)4.0CH, (85)

2.60.50.8

Inactive0.30.050.10.71.03.2

U Hot plate activity, morphine = 1.

Iy great analgesic activity (107). This observation indicates that the usualstructure-activity relationship inherent in the morphine series does notalways hold. To evaluate the importance of a carbonyl group in the6-position, the 4-hydroxy-6-ketone (75), readily available from eithermorphine (108) or by total synthesis (109), was deoxygenated to 76 usingthe Musliner-Gates reagent (100). The 6-ketomorphinan (76) possessesremarkably potent analgesic activity, being three times as potent asmorphine in the hot plate assay (101). For comparison purposes, theun substituted compound 21, without the 6-ketone, has about one-half theactivity of morphine.

Hydroxylation of the 3-position is the most important A-ring substitu-tion in the morphine alkaloids as well as in the morphinans. The 3-hydroxy-6-ketomorphinan (77) was originally synthesized by a rather diffi-cult route from dihydrothebainone (8) via the 4-phenyl ether (110,111).A lengthy total synthesis using a modification of the Gates morphinesynthesis yielded racemic 77 (112). Subsequently, use of the Grewemorphinan synthesis allowed 77 to be obtained from readily availablestarting materials in six steps (113). The methyl ether (78) is readilyobtained either directly from 77 or as an intermediate in the synthesis.Neither 77 nor 78 is as potent as morphine (Table 5-7), but surprisingly, themethyl ether is significantly better as an analgesic.

a

CH3~CIl3

~b

r

~)a

(OM ) b

~~~CH)~O'/~CH)

12 15 81

c /,,\ '\ / \\ d,e, rI\

N-CHO f#o0.> C"H~CH.,O. HO

CH)d '0 C6HS OCH1 /bC"Hc

\\ I In~ \ c 0 d,eCH_O 0

~\\

0

2125 The Morphinans V Structure-Activity Relationships of the Morphinans 213

7 f,c H~3

\\o

80 82Scheme 5-8. Synthesis of I-hydroxy-6-ketomorphinan. Reagents: (a) Fremy's salt, reduc-

tion; (b) benzylbromide; (c) 5-chloro-l-phenyl[lH]tetrazolc, H2/Pd; (d) potassium hydrox-ide; (e) HCHO, hydride, phenyltrimethylammonium mcthoxide.

f-.a

The synthesis of the I-hydroxy-6-ketomorphinan (80) is outlined inScheme 5-8. The synthesis proceeds from the protected morphinan (81).Oxidation with Fremy's salt, potassium nitrosodisulfonate, gives thep-quinone, which is reduced to the hydroquinone. The I-hydroxyl group isselectively benzylated and the 4-hydroxyl group is removed using theMusliner-Gates reagent. Deformylation followed by N- and a-methyl-ation forms I-hydroxy-80 and I-methoxy-6-ketomorphinan 82 (101). Thisreaction pathway is necessary because the Grewe cycIization gives onlyabnormal products (62). In the hot plate assay, the free phenol (80) isinactive, while its methyl ether (82) has about one-third of the activity ofmorphine. The 2-hydroxy-6-ketomorphinan (83) and its O-methyl ether(84) have been prepared from 3-methoxyphenylethyl amine and 3-methoxyphenylacetic acid using the standard Grewe cycIization. Theanalgesic potency is disappointing, being only 5 and 10% of morphine for83 apd 84, respectively (115). The 4-hydroxy-75 and 4-methoxy-6-keto-

79Scheme 5-7. Synthesis of (- )-3-hydroxy-6-ketoisomorphinan from thebaine. Reagents:

(a) Na/NH3; (b) C6HSBr, pyridine, Cu; (c) 5% hydrochloric acid; (d) H2,Pd/C; (e)

deketalization, (f) potassium hydroxide, triethylene glycol.

The isomorphinan derivative (79) of 77 has also been prepared in alengthy sequence starting from thebaine (12). The synthetic sequenceleading to the isomorphinan is outlined in Scheme 5-7, which gives an ideaof the effort that went into the synthesis of some of these molecules (114).The isomorphinan (79) has about 12 times the potency of morphine in thetail flick assay, which makes it about equipotent with the equivalentmorphinan (77).

Compound Rt Rz Analgesic Potency"

92 OH OH 0.1693 OH OCH3 0.594 OH OCzI-I5 1.589 OCH3 OCH3 2.691 OCHzO 0.148 OCH3 OH 0.4

90 OCH3 OCZH5 1.5

a Hot plate test, sc;.morphine = I.

214 5 '['he Morphinans

morphinan 85 are the most surprising monosubstituted 6-keto compoundsto come out of this series. The requisite 4-hydroxy compound (75) isreadily prepared either by total synthesis (109,116) or from morphine(108,117,118). Methylation or acetylation by standard methods furnishesthe O-methyl ether (85) and the acetyl ester (86). The phenol (75) and itsacetyl derivative (86) are approximately equipotent to morphine. How-ever, the 4-methoxy compound (85) has over three times the activity ofmorphine (118,119).

HO

B7 (R1=H, R2=OH)

BB (R1=OH, R2=H)

The requirement of a 6-ketone for strong analgesia in this s~ries isdemonstrable not only by the difference in analgesic potency with the6-deoxy compound (21) but also with the epimeric 6-hydroxyl compounds87 and 88. The 613-aIcohol (87) has 7% of the analgesic activity of the6-ketone (75), while the 6a-aIcohol (88) has 8% (119). Opiate receptoraffinity for 75 is equivalent to that of morphine, while the methyl ether (85)has about one-third the affinity of morphine (119).

Th~ 3,4-disubstituted 6-ketomorphinans, although more complex thanthe singly substituted analogs, were prepared much earlier by reductiveconversion of codeine to dihydrothebainone (8). The derivatives of 8 wereextensively investigated in Japan after 8 was found to retain 40% of theanalgesic potency of morphine (Table 5-8) (120). a-Methylation of 8 ~iv~sthe dimethoxy compound 89, which at 2.6 times the potency of morphIne ISthe most interesting compound in this series (119,120). By simple chainextension of 89 to the 4-ethyl compound (90), half of the analgesic potencyis lost, while bridging with a methylenedioxy group (91) effectivelyeliminates analgesia (117). On the other hand, the diphenol (92) hasone-third the potency of isomer 93. The increased lipophilicity at C-4increases the analgesic activity lO-fold on going from the 4-phenol (92) tothe 4-0-ethyl ether (94). A substantial number of disubstituted 6-keto-morphinans containing a 1413-hydroxyl group have been prepared and arediscussed in a subsequent section on 1413-substitutions.

95


Table 5.8

Analgesic Potency of ~,4-Disubstituted 6-Ketomorphinans

5. Substitutions at Nitrogen The substitution of other organic residuesfor the methyl group in morphinans follows broadly the structure-activityrelationships observed in the morphine alkaloid series. The effect ?fvarious alkyl, arylalkyl, and some functionalized derivatives is presented InTable 5-9. The nor-compound, which contains a secondary amine, is verysimilar to normorphine in terms of centrally mediated analgesia (121). Thesubstantially increased polarity in these types of compounds apparentlyprevents efficient crossing of the blood-brain barrier. As the c.hain !e.ngt.his increased from the methyl group in levorphanol (37), analgesIc activity ISrapidly lost, being nonexistent with n-propyl (122,123) and rapidly risingagain as the chain length is further increased to n-pentyl ~~4,96). Bra?-ching of the alkyl side chain does not bring about any defimtlve change Inanalgesic potency. The absence of analgesic activity with an. n-propylsubstitution is also found in morphine, since the compound functIons as anopiate antagonist (122,123). The n-propyl derivative is a potent antagonistof morphine analgesia in the rat but a weak antagonist of respiratorydepression in the rabbit (122). The cyanoalkyl substit~ent has beenreferred to as paradoxical, increasing potency severalfold m some classesof opiates and slightly or not at all in others. In the morphinans, :hecyanomethylene decreases analgesia somewhat. The cyanoethylene denva-tive, however, has lO-fold the analgesic potency of levorphanol and 47-foldthat of morphine (124).

216

Table 5-9

5 The Morphinans

The Effect of N-Substitution on Morphinan Analgesia

RMorphine

AntagonismRelative

Analgesic Potency.

HCH3 (levorphanol)~HsII-C3H7n-C4H9n-CsHIICH2CH2CNCH2CNCH2C6Hs(CH2hC6Hs(CH1hC6Hs(CH2)4C6HSCH2COC6Hs(CH2hCOC6Hs

O.03b50.2o2647<0.6Inactive30.020.136.50.02

Yes

" Morphine = 1.b Tail flick test.C Hot plate test.

The introduction of other oxygen or nitrogen functions into the sidechain leads to a substantial reduction in or elimination of analgesicproperties. The use of arylalkyl substituents also parallels the observationsmade in the morphine series; a phenethyl group is the best substituent,having three times the activity of morphine (34,121). Substituents on thearomatic ring can further increase the analgesia. The phenacyl derivative inthe morphinan series is substantially more potent than morphine inhumans (125) and has substituted for morphine in addiction studies (126).The same compound in the morphine series is essentially inactive.

The use of /3,y-unsaturated or cycloalkylmethylene substituents inplace of the nitrogen methyl group furnishes the same type of narcoticantagonist analgesic found in the morphine alkaloids. While the n-propylcompound is an antagonist, it has been little studied. The N-allyl com-pound, levallorphan (Lorfan), on the other hand, is used clinically.Levallorphan is a potent narcotic antagonist (Table 5-10) that is used to

L


Table 5-10

The Effect of N-Alkenyl, Alkynyl, and CycloalkylmethyleneSubstitution on Morphinan Analgesia and Opiate Antagonism

RRelative

Analgesic Potency.Relative Morphine

Antagonistic Potencyb

n-C3H7-CH2CH=CH2

(levallorphan)

-CH1C==CH-CH1CH=C(CH3h

-CHz--<J(cyclorphan)

-CHz-<>

o1.4

Active1.3

-0.11.3

11.4

-1Inactive2

40 o--" r"'r{ 4;,,,;..J

(.>-

~l",t.J'7).-.tth;a Mouse writhing assay, morphine = 1.b Tail flick antagonism, nalorphine = I.

counteract the respiratory depression caused by narcotic overdose (127).However, by itself, in common with its morphine analog nalorphine,levallorphan causes respiratory depression (127). Although a potentantagonist of morphine analgesia (128), it also has a strong analgesiceffect, although it is not useful clinically because of its nalorphine-likepsychotomimetic side effects (46). The propargyl compound is as effectiveas nalorphine in antagonizing both morphine and phenyl piperidine opiates(123) and has been used as an analgesic in patients with postoperative pain(123,129). In the morphine series, a dimethylallyl substituent yields amixed agonist-antagonist, nalmexone. In the morphinan series, thedimethylallyl compound is a potent analgesic causing mild respiratorydepression but no narcotic antagonism. Its addictive liability is equivalentto that of morphine (123,130).

In the cycloalkylmethylene substitution, the cyclopropylmethylene ana-log (cyclorphan) (60,99) is a potent antagonist in animals (131) and asurprisingly strong analgesic in animals as well as in humans (132).However, cyclorphan produces a high incidence of nalorphine-like psycho-tomimetic effects, which precludes its use as an analgesic. The related

Relative OpiateRelative Antagonistic

RJ Rz Analgesic Potency" potencyb

H CPM< 1.25 InactiveCH) CPM 0.1 0.1CH) CBMd 0.7 InactiveCH) Allyl 0.3 Not dose responsive

218,

5 The Morphinans

Table 5.11

Mixed Agonist-Antagonist N-Substitution in the6-Ketomorphinans

a Mouse writhing assay, morphine = I.b Morphine tail flick antagonism, naloxone = I.< Cyclopropylmethylene.d Cyclobutylmethylene.

cyclobutylmethylene morphinan, on the other hand, appears to be a pureagonist without any antagonist properties (133).

The effect of nitrogen substituents known to convert agonists to mixedagonist-antagonists or pure antagonists has been studied in the 4-hydroxy-and 4-methoxy-6-ketomorphinan series (l18,134). The phenolicN-cyclopropylmethyl derivative (Table 5-11) has potent analgesic activitywithout narcotic antagonist properties (118). Its methyl ether has lflOththeactivity of both morphine and naloxone (134). The cyclobutylmethylenederivative is similar to the 3-hydroxy compound (Table 5-10) in that it is apure agonist (107,134).

The use of heterocyclic alkyl substitutions has led to extremely strongenhancement of analgesic activity over that observed with the N-methylgroup (Table 5-12). The use of thienylethyl and furylethyl substituentsgives morphinans 50 to 100 times more potent than morphine (124).Similar, though less potent, enhancements are observed with other heter-ocycles. The furylmethylene compounds present a striking contrast. Bothunsubstituted compounds are weak pure antagonists. However, the addi-tion of a methyl to the furan ring converts both positional isomers into pureagonists with three to five times the potency of morphine (134). Aninteresting extension of both the phenylethyl and heterocyclic side chains is

L

V Structure-Activity Relationships of the MorphinansU

Table 5-12 f

219

The Effect or N-Heterocyclic Alkyl Substitution on MorphinanAnalgesia

HO

RRelative Analgesic

PotencyMorphine

Antagonism

50"

100

0.25<

5 {' t!'I'~ n 1

0.4

3

U Hot plate test, morphine = 1.I>Writhing test.C Tail clip antagonism, nalorphine = 1.

compound 95 (p. 214), which combines a maleimide substitution on aphenylethyl side chain (135). Compound 95 is one of a series preparedin an effort to obtain a receptor agonist, containing a Michael acceptor,that bonds covalently to the opiate receptor. Although 95 possesses one-fifth the activity of morphine, it is also an antagonist. However, 95 doesnot bond to the receptor in a covalent manner (135).

Rl

Relative Relative OpiateAnalgesic Antagonist Receptor

RI R2 Potency Potency Affinity (nm)

3-0H CH3 4(Ievorphanol)

2-0H CH3 0.02 400

4-0H CH3 0.2 60

3-0CH3 CH3 0.5 2,000

(levomethorphan)2-0CH3 CH3 <0.001 > 10,0003-0H Allyl 0.34 4

(levallorphan)2-0H Allyl Inactive 0.02

3-0H CPM" 2.5 1.5 004

(cyc1orphan)

2-0H CPM 0.1 0.04 30

4-0H CPM 0.08 0.02 35

H CPM 0.2 <0.05 200

3-0CH3 CPM 0.8 300

2-0CH3 CPM rnactive 10,000

" CPM = cyc1opropylmethylene


The effect of variation of N-substitution in the presence of a 1413-hydroxyl group is discussed in Section V,B,3.

B. The Effect of Substituents in Nonfunctionalized Positions onMorphinan Analgesia

Since a substantial amount of the structure-activity relationship ofmorphine was known before the Grewe synthesis made a wide variety ofmorphinans available, the substituents introduced into the various posi-tions of the morphinan ring have reflected the morphine structure-activityrelationship. As a result, less synthetic effort has been expended but morejudiciously targeted molecules have been made.

1. Aromatic A -Ring Substituents and Their Influence on MorphinanBiological Activity An initial indication of the influence of A-ring substi-tuents on the analgesic activity of 6-keto-morphinans was described inSection V,A,3. The broad trend indicated there, where the 3-phenol wasthe most potent, followed by the 4-, 2-, and I-phenols, has been confirmedin a study where substituents were introduced in both the agonist andantagonist morphinan series (136). In addition, the biological activitieshave been correlated with opiate receptor affinity (Table 5-13). As ex-pected, the 3-hydroxymorphinan in each N-substituted series is by far themost potent with respect to receptor binding as well as pharmacologicalactivity. Displacement of the phenolic hydroxyl group to the 2- or4-position decreases opiate receptor binding affinity by 30- to 100-fold.However, the retained affinity is quite significant. It is interesting that thedeoxy analog of cycIorphan demonstrates significant binding affinity, albeit500 times weaker than that of cycIorphan. Alkylating the hydroxyl groupby methyl ether formation reduces receptor affinity at least 100-foldcompared to that of the parent phenol (42,137).

It is apparent that the correlation between binding affinity and pharma-cological, analgesic, and opiate antagonistic potency is excellent. The onlyexceptions are the methyl ethers, which in all cases are considerably morepotent analgesics than would be expected from their binding affinities. Thisis probably due to a partial metabolic de methylation in vivo, which issimilar to that of codeine (138).

Earlier work indicated that a I-methyl or a 2-methyl group in racemor-phan yields analgesics with 0.5 and 1.7 times the activity of the unsubsti-tuted parent, respectively (37, R = H)

C!!...)' LI~W3~)2. The Introduction of Various Substituents at Positions 5 to 10

Metopon, 5-methyldihydromorphinone, is considered to be one of thebest morphine-based analgesics developed in terms of potency without sideeffects (139). An intermediate in the synthesis of metopon (97), which is

L


Table 5-13

The Effect of A-Ring Substituent Positions on Morphinan Analgesia

readily prepared by the reaction of dihydrothebaine (96) with methylgrignard, has the requisite 513-methyl group (140). O-Methylation givesthe 513-methyl-6-ketomorphinan derivative (98) (Scheme 5-9), which has1.5 times the activity of morphine (141). The analgesic activity is compara-ble to that of metopon, but the pharmacological profile of 98 has not beendescribed.

In contrast to the reaction of dihydrothebaine with grignard reagents,the addition of lithium dimethylcuprate to thebaine results in the stereo-specific introduction of a 713-methyl group together with epoxide ringopening (142). Controlled hydrolysis then leads to either the morphinan orisomorphinan series (Scheme 5-10) (142). Reduction of the enone double

a> H)

12

/ le.

222

96

b ).

5 The Morphinans

a

97

98Scheme 5-9. Synthesis of a 5-methylmorphinan. Reagents: (a) MeMgI; (b) phenyl-

trimethylammonium chloride.

CH) H)

CH) CH)O

.Scheme 5-10. Reaction of thebaine with methylcuprate. Reagents: (a) lithium

dlmethylcuprate; (b) aqueous acetic acid; (c) 5% hydrochloric acid.

L


Table 5-14

The Effect ofa 7-Methyl Group on 6-Ketomorphinan andlsomorphinan Analgesia

bond is stereospecific in both series, forming the 7a-methylmorphinanand the 713-methylisomorphinan. In order to prepare the 3-oxygenatedcompounds, the 4-hydroxyl group is reductively removed. The nitrogensubstitution is varied by preparing the nor-compound. The morphinanand isomorphinans containing either a 3-hydroxyl or a methoxyl substit-uent in both the agonist and antagonist series are potent analgesic agents(Table 5-14) (143). In general, the introduction of a 7-methyl group doesnot substantially alter the analgesic potency of the parent unsubstituted

RI Rz

MorphinanH CH)H CPM'H CBMdCH) CH)CH) CPMCH) CBM

IsomorphinanH CH)H CPMCH) CH)CH) CPM

Relative

R, Rz R) Analgesic Potency"

CH) CH) CHO 0.2 ( Ir~1f Ilf6 JCH) CH) CH(OH)(CHzhCH) (101) 130 '<!

CH) CH) CO(CHzhCH) 1

H CH) CO(CHzhCH) 17

CH) CPMb CH(OH)(CHzhCH3 4

224 5 Tli'e Morphinans

morphinan, nor does it significantly increase the analgesic strength overthat of morphine. The reason for the interest in a single substituent at C-3is that 3,4-disubstituted morphinans 99 and 100 have only 0.2 times theanalgesic potency of morphine in the writhing assay and very weakmorphine antagonism (144).

99 (R=H)

100 (R=CH3)

In a simple model of the thebaine Diels-Alder adducts, a diastereomeric7-carbethoxy group has been introduced into various N-substituted 6-keto-morphinans and isomorphinans. In contrast to the tremendous potencyenhancements with the Diels-Alder adducts, the results with the morphi-nans have been disappointing (Table 5-15). The analgesic potencies varyfrom weak to approximately that of morphine, while the antagonistpotencies are all substantially less than that of nalorphine (145). In anextension of this work, a series of compounds has been prepared in which a6-double bond in the isomorphinan residue generates a molecular volumesimilar to that of the Diels-Alder adducts (146). Insertion of a substituted7-alkyl group would prepare a simpler analog of the Diels-Alder adducts.Of the compounds prepared (Table 5-16), the target compound 101,containing a secondary pentyl alcohol, is 130 times as potent as morphine(146). In contrast, however, the BC-cis morphinan analog is inactive.

The 8-alkylmorphinans are readily prepared from morphinan 102, whichis easily prepared from thebaine. Hydrolysis of the enol ether yields themorphinan enone (103) (Scheme 5-11), which undergoes organocuprateaddition to stereospecifically introduce the 8f3-alkyl substituent (104) (147).An extensive series of these compounds has been prepared with a 3-oxygengroup and varying nitrogen functionality. Table 5-17 shows a representa-tive variety of the compounds and the associated biology. On the whole,analgesia and opiate antagonism decrease with increasing chain length atC-8. Significantly, none of the 8-alkyl derivatives is as active as itsunsubstituted parent (147). However, the biology is sufficiently encourag-ing to cause investigators to study the effect of 6-ketone modification (148).The most interesting compound is 106, which has potent mixed agonist-

l

Table 5-15

7-Carbethoxy-6-ketomorphinans and -isomorphinans

Isomorphinan

RelativeAnalgesicPotency"

RelativeOpiate Antagonist

Potencyb

1.00.20.70.2

<0.1'<0.1'

Not tested0.3

<0.1'Not tested

<0.3'<0.3'

1.30.2

<0.1'<0.1'

Not tested0.3

Not tested<0.1'

U Mouse writhing test, morphine = I.b Rat tail ftick antagonism, nalorphine = 1.e Cyc1opropylmethylene.d Cyc1obutylmethylene.,

Calculated from the highest dose tested.

Table 5.16

Analgesic Potencies of 7-Substituted 6,7-Didehydroisomorphinans

" Mouse writhing test, morphine = I.b CPM = cyc1opropylmethylene.

R1

Relative Relative OpiateRl R2 R3 Analgesic Potency" Antagonist Potencyh

H CH3 CH3 0.8 Not testedH CH3 CH2CH3 0.9 Not testedH CH3 (CH2)3CH3 Inactive Not testedCH3 CH3 CH3 1.6 Not testedCH3 CH3 CH2CH3 0.65 Not testedCH3 CH3 (CH2)3CH3 0.1 NO! testedH CBMe CH3 7 0.9H CBM CH2CH3 4 3H CBM (CH2)3CH3 2 0.3CH3 CBM CH3 1.5 0.2CH3 CBM CH2CH3 0.15 InactiveCH3 CBM (CH2)3CH3 0.1 Inactive

a Mouse writhing test, morphine = 1.b Rat tail flick antagonism, nalorphine= 1.e CBM = cyclobutylmethylene.

'>a

102103

b>

Scheme 5-11.104

Reagents: (a) 25% hydrochloric acid, 100°C; (b) lithium dimethylcuprate.

Table 5-17

8-Alkyl Substituents on Morphinan 6-Ketones


antagonist properties. Compound 106 is four times as potent as morphinein the mouse writhing assay and equivalent to nalorphine as an antagonist.In contrast to the 6-ketone, 106 containing a methylene group in place ofthe 6-ketone does not substitute for morphine in drug-dependent monkeys(148).

A series of 813-alkyl-7a-methylmorphinan 6-ketones has been synthe-sized by organocuprate addition to the 7-methyl analogs of 103. In general,the 7,8-disubstitution does not offer an advantage over the unsubstitutedparents either in the agonist or the antagonist series (143).

Early work on the morphinans, stemming mainly from the Gates totalsynthesis, allowed access to the lO-hydroxy (107) and lO-keto (108)morphinans. These compounds do not possess any analgesic activity (34).

106 107 (R=OH)

lOB (R= =0)

3. The Importance of a Hydroxyl Group at C-14 In the morphine-based analgesics, the presence of a 1413-hydroxyl group usually increasesthe analgesic potency and decreases the opiate side effects. Morphinananalogs of all the important morphine derivatives have been prepared bytotal synthesis. In the agonist series, the 3-hydroxy derivative has five timesthe activity of morphine (Table 5-18) (149). Shifting the phenolic hydroxylto position 4 retains the activity but, as in common with the morphinans,the methyl ether is still potent (150). The effects of alkyl chain length onnitrogen parallel the observations made in the morphine series. As a result,a series of alkyl and allyl substituents show mixed agonist-antagonistactivities. The most important of these is the cyclobutylmethylene deriva-tive butorphanol (64), which has both significant analgesic actions andantagonistic activity comparable to that of naloxone (151,152). Butorpha-nol has a low potential for physical dependence in both humans andanimals (151,153). Like many of the mixed agonist-antagonists, butorpha-nol produces some degree of dysphoria and psychotomimetic effects (154).

In contrast to other alkyl substituents, a cyclopropylmethylene groupresults in a relatively clean antagonist, oxilorphan (64,155). The presenceof a 14-hydroxyl group increases the potency in antagonists and decreasesthe intensity of the unpleasant disorienting side effects. However, the

228

Table 5-18

5 The Morphinans

The Analgesic and Antagonistic Activities of 14-Hydroxy Substituted Morphinansand Isomorphinans

RlMorphinan

1Isornorphinan

RelativeAnalgesic Potency.

Relative OpiateAntagonist potencyb

Morphinan3-0H3-0H4-0H4-0CH33-0H

(oxilorphan)3-0H

(butorphanol)3-0H3-0H3-0H3-0H3-0H

Isomorphinan3-0H3-0H3-0H3-0I-!

CBM'

EthylPropylAllyl3,3-DimethylallylPropargyl

CH3CPMCBMAllyl

0.025IeIe

0.04

10

0.80.010.0150.01

0.10.050.07

<0.01

<0.01<0.01

Inactive4.5

0.030.080.2

<0.010.1

<0.010.020.010.02

.Mouse writhing test, morphine = I.h Antagonism of oxymorphone-induced Straub tail, naloxone = I.e Hot plate assay, morphine = 1.

"CPM = eydopropylmethyl.,CBM = cydobutylmethyl.

presence of an oxygen bridge in morphine and its analogs promotesmetabolic deactivation at the 3-position. In human studies, oxilorphan hasbeen' found to be very long-acting and to have only one-eighth the sideeffect activity of the benzomorphan cyclazocine (133,156). However,disturbing psychotomimetic effects have been reported with a high sub-cutaneous dose of oxilorphan (157).

I

L


47a )

109

b----

c-110

Scheme 5-12. Reagents: (a) trifluoroacetic anhydride; (b) m-chloroperbenzoic acid; (c)sodium t-pentoxide in hot benzene.

Since these 14-hydroxymorphinans are prepared by a total synthesis thathas significant flexibility, it is possible to prepare the 14a-hydroxy-isomorphinans readily (Scheme 5-12) (158). The key to the syntheticaccess to the 14a-hydroxy compounds is the stereospecific epoxidation ofthe hydrophenanthrene (109), which is readily accessible from the commonintermediate (47) (cf. Scheme 5-5). Ring closure then forms the isomorphi-nan. None of the isomorphinan derivatives has significant analgesic orantagonistic activity in comparison with the epimeric morphinan (149).

The introduction of a 6-ketone into the 14-hydroxy morphinan seriesproceeds by reduction of 14-hydroxydihydrothebainone (159). A largeseries of 3,4-disubstituted-6-ketomorphinans has been prepared (160).The monosubstituted compounds are obtained by suitable reductivedeoxygenation from the disubstituted compounds (107,159). The presenceof the 6-ketone tends to increase the analgesic potency over that of theunsubstituted parent (Table 5-19). For instance, the A-ring unsubstitutedcompound is twice as potent as morphine (107). In contrast to oxilorphan,the 6-keto derivative and its O-methyl ether have potent anti nociceptiveactivity (161-163). Shifting the methoxyl group to the 4-position alsoincreases the agonist activity. Surprisingly, a series of 4-methoxy-6-keto-morphinans containing allyl and cyclopropylmethyl nitrogen substituentslack either agonist or antagonist properties (150). The 3,4-disubstituted

Relative OpiateRelative Antagonistic @Sf)R[ R2 R] Analgesic Potency. Potencyb

H H CH] 2 r~F1 }Z::;OCH] H CH] 3 ~H)OH H CPM< 0.2 (?) )-c'1OCH] H CPM '''C-(CH) C H

2.7 ) ~IJJH

2 2 6 5H OH CH] 1.5H OCH] CH] 5.4

I SO CH)O OCH)H OCH] AJlyl Inactive 0.01 J0}-}V3H OCH] CPM Inactive 0.03 11) 120 (R=CPM)OCH] OH CH] 0.9~OCH] OCH] CH] 24 [..f d..'D) 121 (R=CBM)

OCH] OCH] CH] (6a-OH) 0.4OCH] OCH] CH] (6,B-OH) 0.7


Table 5-19

Analgesic Potencies of 14-Hydroxy-6-ketomorphinans

.Hot plate test, morphine = I.b Naloxone = 1.< CPM = cyclopropylmethylene.

c?mpounds are ~otent analgesics, and a large number have been synthe-sIzed (!20): The Importance of the 6-ketone is evident when compared tothe eplmenc 6-hydroxyl compounds (Table 5-19). The alcohols possessonly 2-3% of the analgesic potency of the 6-ketone (120).

C. Ring Additions, Contractions, Enlargements, andMovements in the Morphinans

The. Diels-~Ider adducts of thebaine have led to extremely potent

morphme agoms~s and an.tago~ists (Chapter 3, Section III). Surprisingly,however, there IS very lIttle mformation on the Diels-Alder additionreactions of ,B-dihydrothebaine (16) and dienophiles. The reaction of 16~ith methyl vinyl ketone yields the adduct (111) (164). Compound 16 andItS3-acetate react with acetylenic dienophiles, via a zwitterionic intermedi-ate, t? for~ hydr~phena?threnes. rather than Diels-Alder ad ducts (165).DespIte thIs paucIty of mformatlOn, an efficient synthesis of an analog


", COCH)

111 112

(112) of 16, in which the nitrogen has been translocated from C-l7 to C-16,has been reported (166). The analog (112) has subsequently been con-verted into adduct 113 by Diels-Alder addition followed by grignardaddition (166). There have been no reports of biological testing for any ofthese adducts.

A 5,6-benzo-annulated analog of racemorphan has been prepared, asillustrated in Scheme 5-13. Condensation of the naphthylethylamine (114)with a glycidic ester (115) furnishes the Grewe intermediate (116), whichcannot be cyclized. After N-methylation, 117 is converted to the morphi-nan (118) (167). The cyclopropylmethylene derivative is further convertedto the 5,6-cyclohexano compound (119). These analogs, when compared tothe mixed agonist-antagonist pentazocine, show that the N-methyl com-pound (118) has two times pentazocine's analgesic activity, while 119 has0.2 times its analgesic activity but equivalent antagonistic activity (167). Aseries of 6,7-substituted l4-hydroxymorphinans has been synthesizedaccording to the method shown in Scheme 5-5. Of the CE-transcyclohexano derivatives, neither the cyclopropylmethylene (120) nor thecyclobutylmethylene (121) compound possesses analgesic activity, while120 is equivalent to naloxone as an antagonist. Compound 121 is inactive asan antagonist (168).


+a,b

114 115

c )

118116 (R=H)

117 (R=CH3)

d,e)

119Scheme 5-13. Reagents: (a) aqueous hydrochloric acid, heat; (b) Eschweilcr-Clark

r~action; (c). 85% phosph~ric acid, 150°C; (d) conversion to N-cyclopropylmethylene; (e)Birch reductIOn and selective catalytic hydrogenation.

Contraction of the C-ring has been accomplished by using cyclopentenyl-ethylamine in place of the corresponding cyclohexenylethylamine in theGrewe synthesis, as shown in Scheme 5-14 (169). The resulting C-nor-morphinan (122) as the racemic mixture lacks analgesic activity. Theoptically active compound has been synthesized in a long sequence from7-oxodihydrothebainone, but no biological activity has been reported(170). The 6-methyl-C-nor (123) and exo-6-methylene-C-nor (124) com-pounds have also been synthesized. Compound 123 is reported to be 19tLmes as active as morphine in the hot plate test (170). ---

.The D-normorphinans can be synthesized by the appropriate modifica-

tIon of the synthesis outlined in Scheme 5-5. The D-normorphinans 125and 126 are both devoid of analgesic activity and do not interact with the


OH

a,b+ 115 )

cJ> ~ '1;-Mil I

/ie'it@ £$ c;J..We; fer- Ct..rk.

iPB 4),3+ ()Cj5/J ,

-r.et-.J1.I, 1/.:<\ {I'HHO

122

Scheme 5-14. Reagents: (a) aqueous hydrochloric acid, heat; (b) Eschweiler-Clarkreaction; (c) hydrogen bromjde.

M>"""'Y ~1"~C/EIl (X = CH3) 125 (X H)

\r«;#:J:;q)! 124 (X==CH2) 126 (X OH)

opiate receptor- (171). Because of this lack of activity, interesting pos-tulates have been made about the mode of interaction of the nitrogen atthe receptor level (172). An X-ray study of 126 has demonstrated that thenitrogen lone pair is oriented toward the aromatic A-ring, while in themorphinans and benzomorphans the orientation is toward the aliphaticCoring. Nitrogen looe pair orientation has therefore been proposed as thekey factor in receptor binding. A mechanism has been proposed wherebythe nitrogen lone pair interacts with an electrophilic site on the receptor,followed by stereospecific electron transfer from the ligand. As a result, theligand itself is oxidized. This type of binding has been termed clastic (172)and has been criticized (173,174). In the benzomorphans, the biologicalresults from rigid analogs in which the nitrogen lone pair is directed eithertoward or away from the A-ring does not support the theory of clasticbinding (175). Nevertheless, investigations continue in this area (176).


)a

128

)c

e f,g,h

i,q,; )

RO129 (R=CHJ)

1JO (R=H)Scheme 5-15. Reagents: (a) dimethylaminoethylchloride; (b) LiCH2C02Et; (c) p-toluene

sulfonic acid; (d) H2,Pt; (e) Ba(OHh, then polyphosphoric acid; (f) ethyl chloroformate;(g) hydrochloric acid; (h) formaldehyde; (i) LAH: (j) H2-PdjC.

The C-homo morphinan (127) has been synthesized from cycJoheptenyl-ethylamine using the procedures shown in Scheme 5-14 (169,177,178).The compound is as active as morphine but is more toxic. A C-homo-morphinan in which an additional methylene group has been insertedbetween the nitrogen and the B-ring has been synthesized as outlined inScheme 5-15 (179). Starting from a phenylcycJohexanone (128), thetetracycJic ring system is constructed in a nonconvergent linear fashion to

L


127 131 (R = OCHJ)132 (R = OH)

form the 3-methoxy (129) and 3-hydroxy (130) C-homomorphinans. Theequivalent isomorphinans 131 and 132 ar~ similarly pr~pared (179). Thehomomorphinans 129 and 130 have 0.35 times and 1.5 times the hot plateactivity of morphine, respectively, while the homoisomorphinans 131 and132 had about one-third the potency of the stereoisomeric homo-morphinans (180). .. .

There have been a few examples of moving one of the termlnt of thepiperidine D-ring in morphinans. One of the first .is the movement of thecarbon terminus to C-14, which also causes the D-nng to contract. The newring system has been termed metamorphinan and is readily prepared fr~mthebaine (12), as indicated in Scheme 5-16 (181). Thebaine readily

a bThebaine (12)

133

c,d,e )

HO

134 135Scheme 5-16. Reagents: (a) SnCI2, hydrochloric acid; (b) H2-Pd/C, 18% hyd~ochloric

acid; (c) 2,4-dinitrophenyl chloride; (d) Birch reduction: (e) pyridine hydrochlonde.

236,

5 The Morphinans

rearranges to metathebainone (133); the latter is reduced to 134, which hasthe BC-rings in a trans relationship. Removal of the phenolic group at C-4and O-demethylation yields metamorphinan (135), which actually belongsto the isomorphinan series. Despite these rather radical changes, 135retains 10% of the analgesic potency of morphine in the mouse writhingtest (181). Movement of the nitrogen terminus to C-8 leads to themorphinan analog (136), which has been synthesized by a method similarto that shown in Scheme 5-15. Compound 136, however, possesses onlyweak analgesic activity (182). Simultaneous ring expansion of the D-ring

H

136 137

16

HO138 (Des-N-morphinan) 140

and movement of the N-terminus to C-14 forms the derivative (137), whichdoes not have any analgesic action (183). Compound 130, which is thecorresponding morphinan derivative of 137, is more potent than morphine(180).

The variety of chemical manipulations leading to the addition of rings,ring enlargements, and contractions, as well as the shifting of the D-ringtermini, have not led to a substantially improved analgesic or biologicalprofile over that of morphinan itself. On the contrary, most changes havestrongly diminished or eliminated the analgesic activity.

D. Movement of the Nitrogen within the MolecularFramework and Heteroatom Insertion

The effect of moving the position of the amino group in morphinans hasbeen extensively studied by Japanese scientists. They have used a conven-tion whereby the compounds are named as aza-derivatives of des-N-

L


CH2---@oCH3

00 d,e)

f

139

Scheme 5-17. Reagents: (a) p-methoxyphenylmagnesium chloride; (b) dehydration;(c) H2-Pd/C; (d) CH3I; (e) HrPt; (f) 48% hydrogen bromide reflux.

morphinan (138) (184). The syntheses of t~ese molec~les have all beensimilar, using either a phenyl or benzyl substItuted, partIally hydr~genatedquinoline or isoquinoline and subjecting it to the Grewe cycl~tlOn. Forinstance, the 6-azades-N-morphinan (139) has been prepared as Illustrate~in Scheme 5-17 (185). In this synthesis, a substituted benzyl group ISi~troduced at C-5 in the isoquinoline, which, after reduction to the Greweintermediate, cyc1izes readily to 139 (185). The 6-aza derivative does notpossess analgesic activity (186). . .

The 7-azades-N-morphinan (140) has been prepared by additIOn of the.grignard in Scheme 5-17 to the 8-position of an isoquin~line followed byGrewe cyclization (187). The distances between the ammo and hydrox~lfunctional groups and the quaternary carbon in 140 are the same as I.nracemorphan (37). However, the analog possesses only weak. analgesIcproperties (188).. The 8-aza-analog has bee~ prepared ~s shown. I~ Scheme

5-18. A phenyl substituent is introduced mto the apical position of an8-carboxyperhydroquinoline to yield 141. Ring closure of 141 forms theB-ring of the morphinan (142), which is converted into the 8-azades-N-morphinan (143) (189). Further investigation has demonstrated that 143has the same stereochemistry as morphine (BC-cis, CD-trans) (190). As aresult, the 3-hydroxy compound (144) has been prep.ared (191). Com-pound 144 has about 10% of the activity of. morp~me (191). The. 3-hydroxy-15-aza- and l~-azades-N-morphi~ans, ~n.keepmg with the earlierobservations, do not possess any analgesIc actIVIty (192-195). The most

238

R

5 The Morphinans

R

141

R143 (R=H)

144 (R=OH)Scheme 5-/8. Reagents: (a) acrylonitrile; (b) ethyl oxalate, NaH; (c) base; (d) H2-PdfC;

(e) H2-Pt; (f) Eschweiler-Clark reaction; (g) hydrochloric acid, then polyphosphoric acid;(h) Huang-MinIon.

142

potent analgesic activity is found in the 9-azades-N-morphinan derivative(145), which is approximately equal to that of morphine but is much moretoxic (196). A compound (146) has been prepared that is not only a16-azades-N-morphinan but has the N-terminus of the O-ring moved fromC-9 to C-14 (197). Like most of these derivatives, 146 does not possessanalgesic activity (197). The azades-N-morphinans, with the exception of145, have been disappointing on the basis of their biological activities.However, the biological activity observed in 145 has served as the basis formaking aza analogs.

V Structure-Activity Relationships of the Morphinans ZJ9

a,b>

d,e

c---+

f

147 (R=CH3)

148 (R=CPM)

Scheme 5-/9. Reagents: (a) ethyl bromoacetate; (b) NaOH; (c) hydrazine; (d) benzylchloride, NaH; (e) lithium aluminum hydride; (f) formaldehyde.

A nitrogen heteroatom has been introduced into the morphinan deriva-tive (145) with the expectation that an excellent analgesic activity wouldbe observed without addiction liability (198). Among the several methodsfor synthesizing the desired compound, 147,. is that. shown in Scheme 5-19(199). Although the biological results obtained wIth 147 have no.t beenreported, the N-cyc1opropylmethy! derivative (~48) has been descnbed as"a fantastic analgesic" (200). The levo-enantlOmer of 148 has approx-imately five times the analgesic activity of pentazocine in the writhing assaybut only 10% of the antagonistic properties of levalorphan (200,201).


HO HO

145 146

149 156

A different type of aza-derivative has been obtained by the Beckmannrearrangement of dihydrothebainone (8) to form the azalactam (149),which, however, again does not have any analgesic activity (202).

The introduction of an oxygen atom into the C-ring of the morphinanmolecule has resulted in some potent analgesic agents, in contrast to theaza series. The synthetic scheme is illustrated in Scheme 5-20. Thebenzomorphan derivative (ISO) is converted to either the 0'-152 or {3-151alcohol, depending on which reducing reagent is used. Hydroborationfollowed by oxidation generates a primary alcohol from the allylic groupthat is ring closed to pyran in the morphinan (154) or isomorphinan (153)series. The reaction sequences employed lend themselves readily to theintroduction of a substituent at C-14 in the morphinan products by allowingthe use of various organometallic reagents. The N-substitution has also~een investigated, with various antagonist and agonist groups beingmtroduced. The biological results indicate that the oxamorphinans are allmore potent analgesics than their oxaisomorphinan counterparts. Addi-tionally, the introduction of the oxa-atom provides a compound equiva-lent to the parent compound plus the addition of a 14-hydroxyl group.Cyclopropylmethylene substitution yields mixed agonist-antagonist activi-ties that are increased by 14-alkyl substitution (203-206). The 6-oxaderivative (155), proxorphan, of cyclorphan is 7-10 times as potent asmorphine in three rodent models of analgesia and has 0.05 times theantagonistic potency of naloxone (207-209). The compound is morepotent and has longer lasting antitussive properties than codeine (210).

A compound (156) that contains a thiophene ring in place of the

V Structure-Activity Relationships of the Morphinans

a,h,c

150

152

HO

241

151

ld,f

153

154

Scheme 5-20. Reagents: (a) sodium borohydride; (b) borane; (c) hydrogen peroxide; (d)methane sulfonyl chloride; (e) diisobutylaJuminum hydride; (f) boron tribromide.

155

aromatic A-ring has been described synthetically, but without any biologi-cal results (211).

In summary, the introduction of oxygen and nitrogen heteroatoms intothe morphinan ring system has been significantly more successful in eitherretaining or increasing the analgesic properties of the molecules than themovement of position 17 of the nitrogen.


VI. The Chemical Anatomy of the Morphinans

The tet:acyclic structure shown in Fig. 5-1 represents the absoluteconfiguratIOn of the analgesically active isomers of the morphinan seriesAll kno~n ac~ive is~mer~ are levorotatory, the dextrorotatory enantio~mers bemg either mactlve or much less active. The dextrorotatorcompounds, ~owever, usually possess antitussive properties.

y

The morphmans have the same absolute configuration as morphine atcarb~n at.oms 9, 13, a~d 14. .On the basis of the structure-activityrelatlO?shlps developed m SectIOn Y, trends for analgesic potency inmorphmans are the following:

1. The B~-trans ring junction found in the isomorphinans can increaseanalgesIa severalfold over the BC-cis junction.

2. The pr.esence of a free or acetylated hydroxyl at C-3 is necessary;alkylatIon decreases the analgesic potency severalfold.

3. A 6-ket.one can .strongly affect analgesic activity. The 3-deoxy-6-ket?ne. IS t~ree tImes as potent as morphine. While the 3-methoxydenv~tlve ]S about equivalent to morphine, the 4-methoxy and3,4-dlmethoxy compounds have three times the activity of theequivalent morphines.

4. Nitrogen substituents of the type CH2-X-aryl in which X ismethylene, CC?, or CHOH and the aryl residue is thienyl, furyl, orphenyl a.re optImal. The thienyl compound is 50 times and the furylIS 1O? tI.mes. as P?tent as morphine. The simpler cyanoethylenesubstItutIOn ISeqUIvalent to furyl.

5. Derivatives containing small aliphatic nitrogen substituents from 3to 5 carbon atoms, such as allyl or cyclopropylmethylene, are potent

CHz, co. CHOH

"Phenyl. thlenyl. ~ - - -/i"\\ /furyl I! \Lx~ CHz

-.'Nitrogen insertion <- - - - - --at C-IG

__

_ ~ CH2CHzCN

N'- cis or trons

.yBC-ring junction._::.-:: _>H or OH at C-14

- - - - -:;.Oxygen insertion at CoBC

:;.CH(OH)(CH2bCHJ at C-7, ,, ,, ,~ \to

Hydroxy or methoxylgroups at C-3, C-4

Fig. 5-1. Potency-enhancing substituents on morphinans.

,,~

Ketone at C-G

l

References 243

mixed agonist-antagonists, strongly paralleling the observationsmade in the morphine series.

6. Substituents at carbon atoms 5, 7, and 8 of the Coring generallydecrease or eliminate analgesia. An exception is the 7a-hydroxy-pentenyl, which is 130 times as potent as morphine.

7. Hydroxyl substitution at the BC ring junction (C-14) enhancesanalgesia over the unsubstituted parent.

8. Ring contractions and expansions usually decrease activity. Excep-tions are the 6-methyl-C-normorphinans, which have 19 times theactivity of morphine, and the C-homo, which is equivalent tomorphine.Movement of the termini of the D-ring eliminates activity.Moving the position of the nitrogen from 17 in the D-ring eliminatesor strongly decreases analgesia.Introduction of an additionalframework, such as a nitrogenstrongly enhance analgesia.

9.10.

11. heteroatom into the molecularat C-9 or an oxygen at C-8, can

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119. A. E. Jacobsen, F.-L. Hsu. M. D. Rozwadowska, H. Schmid hammer, L. Atwell, A.Brossi, and F. Medzihradsky, He/v. Chim. Acta 64, 1298 (1981).

120. I. Seki, H. Tagaki. and S. Kobayashi, J. Pharm. Soc. 84, 280 (1964).121. P. A. Janssen and C. A. M. Van der Eycken, Drugs Affect. Cent. Nerv. Sysi. 2, 25

(1968).

122. H. I. Chernov, J. W. Miller, and G. J. Mannering, Fed. Proc., Fed. Am. Soc. Exp.Bioi. 18, 376 (1959).

123. J. Telford, C. N. Pappadopoulos, and A. S. Keats, J. Pharmacol. Exp. Ther. 133,106(1961).

124. A. E. Jacobsen, K. C. Rice, J. Reden, L. Lupinacci, A. Brossi, R. A. Streaty, andW. A. Klee, J. Med. Chern. 22, 328 (1979).

125. T. J. DeKornfeld, Cllrr. Res. Anesth. 39, 430 (1960).126. H. F. Fraser and H. Isbell, Bull. Narc. 12, 15 (1960).127. J. E. Eckenhoff and S. R. Oech, Clin. Pharmacol. Ther. 1, 483 (1960); J. E.

Eckenhoff, G. L. Hoffman, and L. W. Funderburg, Am. J. Obslet. Gynecol. 65, 1269(1953).

128. C. W. White, Jr., R. Megirian, and P. S. Marcus, Proc. Soc. Exp. Bioi. N. Y. 92,512(1956).

129. S. Archer and L. S. Harris, Prog. Drug. Res. 8, 261 (1965).130. A. S. Keats; quoted in A. H. Beckett and A. F. Casy, ?rog. Med. Chern. 2,43 (1962).131. L. S. Harris, A. K. Pierson, J. R. Dembinski, and W. L. Dewey, Arch. 1m. Pharma-

codyn. 165, 112 (1967).132. L. Lasagna, J. W. Pearson: and T. DeKornfeld; quoted in L. S. Harris, Narc. Drugs:

Biochem. Pharmacol. p. 89 (1971).133. I. J. Pachter, Adv. Biochem. Psychopharmacol. 8, 57 (1974).134. H. Merz, A. Langbein, K. Stockhaus, G. Walther, and H. Wick, Adv. Biochem.

Psychopharmacol. 8, 91 (1974).135. P. S. Portoghese, R. N. Hanson, V. G. Telang, J. L. Winger, and A. E. Takemori, J.

Med. Chem. 20, 1020 (1977).136. H. Schmidhammer, A. E. Jacobson, L. Atwell, and A. Brossi, Heterocycles 16, 1859

(1981).137. L. D. Simon, F. R. Simon, E. Mohasci, L. Berger, and E. J. Simon, Ufe Sci. 28,2769

(1981).138. T. K. Alder and F. H. Shaw, J. Pharmacol. Exp. Ther. 103, 337 (1951).139. N. B. Eddy, H. Halbach, and O. J. Braendon, Bull. WHO 17,569 (1957).140. L. Small, H. M. Fitch and W. E. Smith, J. Am. Chem. Soc. 58, 1457 (1936).141. A. Brossi, L. Atwell, A. E. 1acobson, M. D. Rozwadowska, H. Schmidhammer,1. L.

Fippen-Anderson, and R. Gilardi, Helv. Grim. Acta 65, 2394 (1982).142. D. L. Leland, J. O. Polazzi, and M. P. Kotick, J. Org. Chem. 45,4026 (1980).143. D. L. Leland and M. P. Kotick, J. Med. Chem. 23, 1427 (1980).144. M. P. Kotick, D. L. Leland, 1. O. Polazzi.1. F. Howes, and A. R. Bousquet, J. Med.

Chem. 24, 1445 (1981).145. P. Herlihy, H. C. Dalzell, 1. F. Howes, and R. K. Razdan, J. Med. Chem. 25, 986

(1982).146. 1. Quick, P. Herlihy, and 1. F. Howes, J. Med. Chem. 27, 632 (1984).147. 1. O. Polazzi, R. N. Schut, M. P. Kotick, J. F. Howes, P. F. Osgood, R. K. Razdan,

and J. E. Villarreal, J. Med. Chem. 23, 174 (1980).148. J. O. Polazzi, M. P. Kotick, 1. F. Howes, and A. R. Bousquet, J. Med. Chem. 24, 1516

(1981).149. I. Monkovic, H. Wong, A. W. Pircio, Y. G. Perron, I. J. Pachter, and B. Belleau, Can.

J. Chern. 53, 3094 (1975).

248 5 The' Morphinans

150. H. Schmid hammer. A. E. Jacobson, L. Atwell and A. Brossi, He/v. Grim. Acta 64,2540 (1981).

151. A. W. Pircio, J. A. Gylys, R. L. Cavanagh, J. P. Buyniski, and M. E. Bierwagen,Arch. Int. Pharmacodyn. 220, 231 (1976).

152. J. Castaner and D. M. Paton, Drugs Fur. 2,231 (1977); ibid., Drugs Fut. 2, 330 (197~);B. R. Belleau, Chem. Can. 32, 1 (1980).

153. A. Delpizzo, Om. Ther. Res. 20, 221 (1976).154. R. W. Houde, S. L. Wallerstcin, and A. Rogers, Adv. Pain Res. Ther. 1,647 (1976).155. J. Castaner and D. M. Paton, Drugs FUt. 2, 746 (1977).156. A. W. Pircio and J. A. Gylys, l. Pharmacal. Exp. Ther. 193, 23 (1975).157. J. G. Nutt and D. R. Jasinski, Clin. Pharmacal. Ther. IS, 361 (1974).158. B. Belleau, H. Wong, 1. Monkovic, and 1. G. Pe~ron, l. Chem. Soc., Chem. Commun.

p. 603 (1974); 1. Monkovic, H. Wong, B. Belleau, 1. J. Pachter, and Y. G. Perron, Can.l, Chern. 53, 2515 (1975).

159. Y. K. Sawa and H. Tada, Tetrahedron 24, 6185 (1968).160. 1. Seki, l. Pharm. Soc. lpn. 83,389 (1963); 1. Seki, J. Pharm. Soc. lpn. 84,615 (1964).161. Y. Sawa, S. Maeda, and N. Tsuji, U. S. Patent 3,085,091 (April 9, 1963).162. K. Hirose, A. Matsushita, Y. Kojima, M. Eigyo, J. Jyoyama, T. Shiomi, Y. Tsukinoki,

H. Hatakeyama, K. Matsubara, and K. Kawasaki, Arch. Int. Pharmacodyn. 241, 79(1979).

163. Y. Sawa, R. Maeda, and T. Kada, U. S. Patent 3,738,989 (June 12, 1973).164. K. W. Bentley and J. B. Taylor, unpublished; quoted in K. W. Bentley, Alkaloids

(N. Y.) 13, 75, 120 (1971).165. K. Hayakawa, 1. Fujii, and K. Kanematsu, l. Org. Chem. 48, 166 (1983).166. K. Wiesner, J. G. McCluskey, J. K. Chang, and V. Smula, Can. l. Chem. 49, 1092

(1971).167. J. L. Douglas and J. Meunier, Can. l. Chem. 53, 3681 (1975).168. M. Menard, P. Rivest, B. Belleau, J.-P. Daris, and Y. G. Perron, Can. l. Chem. 54,429

(1976).169. S. Sugaswa and S. Saito, Chem. Pharm. Bull. 4, 237 (1956).170. Y. K. Sawa, N. Tsuji, K. Okabe, and T. Miyamoto. Tetrahedron 21, 1121 (1965).171. B. Belleau, T. Conway, F. R. Ahmed, and A. D. Hardy, l. Med. Chern. 17,907 (1974);

T. T. Conway, T. W. Doyle, Y. G. Perron, J. Chapnis, and B. Belleau, Can. l. Chern.53, 245 (1975).

172. B. Bclleau and P Morgen, l. Med. Chern. 17, 908 (1974).173. A. F. Casey, Prog. Drug Res. 22, 149 (1978).174. S. Shiotani, T. Kometani, Y. litaka, and hai, l. Med. Chern. 21, 153 (1978); T.

Kometani and S. Shiotani, l. Med. Chern. 21, 1105 (1978).175. M. Hori, T. Kataoka, H. Shimuzu, E. Imai, and Y. Suzuki, Heterocycles 20, 1979

(1983).176. V. M. Kolb and S. Scheiner,l. Pharrn. Sci. 73,389,719 (1984); V. M. Kolb,l. Pharrn.

Sci. 73, 715 (1984).177. S. Saito, Chern. Pharm. Bull. 4, 438 (1956).178. H. Henecka and W. Wirth, Med. Chem. 5, 321 (1956).179. S. Shiotani, l. Org. Chem. 40, 2033 (]975).180. S. Shiotani and T. Kometani, l. Med. Chem. 20, 976 (1977).181. M, Gates and D. A. Klein, l. Med. Chem. 10, 380 (1967).182. E. L. May and J. G. Murphy, l. Org. Chem. 19,615 (1954); ibid. 19,6]8 (1954); E. L.

May, l. Org. Chem. 23, 947 (1958).183. H. Kugita, Chem. Pharrn. Bull. 4, 29 (1956).

References 249

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Sugimoto and S. Ohshiro, Chern. Pharrn. Bull. 5, 316 (1957).186. N. Sugimoto, Japanese Patent 3799 (1957).187. N. Sugimoto and H. Kugita, Chem. Pharrn. Bull. S, 67 (1957); ibid. 6, 429 (1958).188. N. Sugimoto, Japanese Patent 30213 (1957).189. N. Sugimoto and S. Ohshiro, Tetrahedron 8, 296 (1960).190. S. Ohshiro, Tetrahedron 8, 304 (1960).191. S. Ohshiro, Tetrahedron 10, 175 (1960).192. N. Sugimoto and S. Ohshiro, Chem. Pharrn. Bull. 4, 353 (186).193. E. Ochiai and K. Harasawa, Chern. Pharrn. Bull. 3, 369 (1955).194. K. Harasawa, l. Pharm. Soc. lpn. 77, 168, 172, 794 (1957).195. N. Sugimoto and S. Ohshiro, Chern. Pharrn. Bull. 4, 357 (1956).196. N. Sugimoto and H. Kugita, Chern. Pharrn. Bull. 3, 11 (1955); ibid. 5, 378 (1957).197. H. Kugita, Chern. Pharrn. Bull. 4, 189 (1956).198. T. Kametani, K. Kigasawa, M. Huragi, and N. Wagatsuma, Chem. Pharm. Bull. 16,296

(1968).199. T. Kametani, K. Kigasawa, K. Wakisaka, and N. Wagatsuma, Chern. Pharrn. Bull. 17,

1096 (1969).200. T. Kametani, K. Kigasawa, M. Hiiragi, N. Wagatsuma, U. Kusama, and T. Uryu,

Heterocycles 4, 41 (1976).201. T. Kametani, K. Kigasawa, M. Hiiragi, N. Wagutsuma, K. Wakisaka, F. Satoh, and S.

Saito, l. Med. Chern. 13, 1064 (1970).202. I. Seki. Chern. Pharrn. Bull. 18, 1269 (1970).203. 1. Monkovic, Can. l. Chern. 53, 1189 (1975).204. Y. Lambert, J.-P. Daris, and 1. Monkovic, Can. l. Chern. 55, 2523 (1977).205. M. Saucier, J.-P. Daris, Y. Lambert, 1. Monkovic, and A. W, Pircio,J. Med. Chern. 20,

676 (1977).206. Y. Lambert, J.-P. Daris, 1. Monkovic, and A. W. Pircio, l. Med. Chem. 21,423 (1978).207. T. A. Montaka, J. D. Matiskella, and R. A. Partyka, U. S. Patent 4,154,932 (May,

1979).208. Anonymous, Drugs Fur. 6, 632 (1981).209. A. W. Pircio and J. P. Buyniski, PharmacologiJt 22, Abstr. 802 (1980).210. J. C. Reiffenstein, R. L. Cavanagh, and J. A. Gylys, PharmacologiJt 22, Abstr. 803

(1980).211. F. Sauter, P. Stanetty, E. Hetzl, and F. Fuhrmann, l. Heterocycl. Chem. 20, 1477

(1983).

6.The Benzomorphans

1. Introduction . . . . ."

. . . . . . . . .. ..."."II. Benzomorphan Syntheses. .. ""..........III. Structure-Activity Relationships in the Benzolllorphan Analgesics

A. The Effect on Analgesia of Alkyl G~oups in Rings Band C . .B. Nitrogen Substitution . ". . . . . . . . . . . . . . . . .C. The Introduction of Oxygen Containing Functions in the B- and C-Rings

of Benzomorphans"

. . . . . . . . . . . .D. A-Ring Substitutions and Replacements . .

". . . . . . . . . . .

E. BC-Ring Enlargements and Contractions . . . . ."

."

."

. . .F. More and Less Complex Benzomorphan Analogs . . . . . . . . . .

G. Nitrogen Movements within the Benzomorphan Nucleus Plus Nor andHomo Derivatives . . . . . . . . . . .

IV. The Chemical Anatomy of the BenzomorphansReferences . . . .'. . . .

". . . . . . .

250252259259273

289295297304

306310311

I. Introduction

It is tempting to say that the benzomorphans originated in a rigorousscientific study of the simplification of the morphine molecular frameworkto uncover the pharmacophore. However, this type of molecule is arelative latecomer to the family of opiate-derived analgesics. For example,the open chain analgesic methadone, which was developed in Germany inthe early 1940s, preceded the benzomorphans. The present simplificationof the morphine skeleton may be visualized as an excision of furan ringoxygen in morphine followed by truncation of the resultant morphinan atthe BC-ring junction (Fig. 6-1). The benzomorphan ring system was firstsynthesized by Barltrop in 1947 (1). The name of the ring system is derivedfrom the trivial name morphan, originally suggested to Barltrop by SirRobert Robinson to denote the 2-aza[3.3.1] ring system (2,3). Barltrop'soriginal benzmorphan designation was subsequently changed, however, bythe editors of The Journal of Organic Chemistry to the current benzomor-phan. The Korean conflict served as a stimulus for the rapid developmentof this type of analgesic. The National Institutes of Health (NIH) in theUnited States was charged with finding adequate, but not necessarilyimproved, substitutes for morphine and codeine. The discovery of Mayand Eddy at NIH that the 6,1I-dimethyl derivative of benzomorphan met

250

Introduction 251

morphine morphinan benzomorphan

Fig. 6-1. A conceptual genesis of the benzomorphans.

the above criterion stimulated intensive investigation of these molecules(4).

There are two common numbering systems for the benzomorphans: (a)the original and still commonly used 6,7-benzomorphan numberin~ and. (b)the Chemical Abstracts numbering system based on the benzazocme nng.In this chapter, the Chemical Abstracts numbering system together with thetrivial name benzomorphan will be used. The Chemical Abstracts name forbenzomorphan, which,escaped unscathed in the Temh Collective Index, is1 2 3 4 5 6-hexah ydro-2 6-methano-3-benzazocine.,

'.', , ,

~ ~-CH3

4' 4 9

3' 0 6 5

2' I'

BenzomorphanNumbering

Chemical AbstractsBenzazocine Numbering

Because of the importance of the alkyl groups at 6 and 11 to theanalgesic properties of the benzomorphans, it. i~ not fe.asibl~ to use theposition substituent approach to structure-actIvIty relatIonsh~ps that .hasbeen utilized for both the morphine alkaloids and the morphmans. FIrst,the important syntheses of this class of compoun.ds will be indic~ted,followed by the effects on analgesia of alkyl groups m the B- and C-nngs,substituents on the aromatic A-ring, nitrogen substitution, and ox~ge.ninsertion. The introduction of oxygen into the alicyclic rings can mImIc14-hydroxylation in morphine, as well as impart interesting opiate receptorselectivities. Ring-expanded and-contracted benzomorphans have also ledto interesting analgesics in this series of opiates.

151 6 The Benzomorphans

II. Benzomorphan Syntheses

In 1947, Barltrop prepared the first benzomorphan using the tetralone(1) (Scheme 6-1) as the starting material (1,2). The quaternary benzomor-phan (2) was prepared as a model for the A-, B-, and D-rings of morphine.Although this synthetic approach was straightforward, the overall yieldwas poor. Following the initial work, which did not proceed beyond thequ~ternary salt (2), May reinvestigated the synthesis using the dimethyl-aml?o ~nalog (5). Bo.th the alkylation of the tetralone and the subsequentcychzahon occurred m low yields, and this approach was abandoned infavor of a route starting with hydratroponitrile (Scheme 6-2). Although thesecond route is much longer, it provides the benzomorphan (3) in 5%overall yield. Starting from hydratroponitrile (4), the overall yield of thetetralone (6) is 60%. The remaining reaction sequence leading to 3 isequal~y. effectiv~. However, this approach is limited to benzomorphanscontaining subshtuents at position 6. Efforts to prepare 6,11-disubstitutedcomp~unds failed when the methyl ketone corresponding to the aldehyde(5) faded to undergo the Knoevenagel condensation (6). The tetraloneroute, however, has remained a useful route to 6-substituted benzomor-phans.

The most widely used approach to benzomorphan synthesis is based ont~e acid-c.atalyzed c~cJization of appropriately substituted tetrahydropyri-dmes. ThIs method IS analogous to Grewe's method for the synthesis of

1

b,e".

2.Scheme 6-1. Original synlh~sis of the benzomorphan ring syslem. Reagents: (a) soda-

mlde, CI(CHzhNEtz; (b) bromine; (c) sodium bicarbonate.

II Benzomorphan Syntheses 253

e,d,e~

4 5

f?

CZ'

~(C"2)2NMe2CH3

6

j, k,l

' ?

3

Scheme 6-2. A more efficient synthesis of the benzomorphans. Reagents: (a) sodamide,Cl(CHzhNMe2; (b) lithium aluminum hydride; (c) methyl cyanoacetate, ammonium acetatein acetic acid; (d) H2/Pt; (e) hydrochloric acid; (f) polyphosphoric acid; (g) hydrobromic acid;(h) bromine; (i) ammonia (aqueous); (j) pyrolysis; (k) hydrochloric acid in ethanol; (I)

Huang-Minion.

morphinans from substituted tetrahydroisoquinolines (d. Chapter 5,Section IV,A) (7). This route is especially useful, since it allows thepreparation o( 6,1l-disubstituted benzomorphans that are more effectiveanalgesics and are inaccessible by the tetralone route. The first examples ofbenzomorphans prepared by the Grewe reaction are the 6,1l-dimethylderivatives 9 and 11 (Scheme 6-3) (6). Addition of either benzyl grignardor p-methoxybenzyl grignard to 3,4-dimethylpyridine methiodide (7),followed by reduction of the resultant sensitive dihydropyridine, gives thetetrahydropyridines 8 and 10. The grignard has added to the morehindered position of the pyridinium salt. Subsequent cycJization of 8 withphosphoric acid gives the 6,1l-dimethylbenzomorphan (9) in 20% overallyield. Analogously, the tetrahydropyridine (10) undergoes cycJization and


a,b- <X:::-fc5\ R

CH3 ~7 8 (R

10 (R

HI

OCH3)

9 (R = HI11 (R = OH)

Scheme 6-3. Grewe cyclization of benzyltetrahydropyridines. Reagents: (a) benzyl grig-nard; (b) borohydride; (c) 85% phosphoric acid.

ether cleavage to furnish the 8-hydroxy-6,1l-dimethylbenzomorphan in14% yield from 7. The Grewe synthesis of benzomorphans is very general,and literally hundreds of compounds have been prepared by this method.In many cases, the greatest synthetic challenge has been the preparation ofthe appropriately substituted pyridine.

The Grewe benzom01'phan products 9 and II in Scheme 6-3 are drawnwith the alkyl groups cis with respect to the B-ring. This cis stereochemistryhas been termed a by May and Eddy (8). Analogous to the Grewemorphinan synthesis, small amounts of the trans, with respect to theB-ring, or {3 isomer can also be isolated in many cases. The initialassignment of stereochemistry was based on analogy with the provenmorphinan BC-ring stereochemistry (7). The isomerism in the benzomor-phans has been extensively studied because of the important pharmacolo-gical differences between the a and {3series. Initially, differentiation wasbased on the rate of methiodide formation where by the less hindered aisomer quaternized 5-10 times faster than the more hindered {3 isomer(9). Subsequently, proton nuclear magnetic resonance NMR studiesdemonstrated that the II-methyl group in the cis-isomer resonates about25 Hz upfield from the lla-methyl (9). These suppositions were thensupp.orted by X-ray crystallographic studies (10).

I

L


a- b--

12

14 (~I 13 (0:)Scheme 6-4. Reagents: (a) methyl grignard. then pyrolysis; (b) thionyl chloride, pyridine;

(c) H2/Pt, HCI04; (d) H2/Pt.

Because the {3isomers usually occur as a minor product in the Gre~esynthesis, methods have been developed to make them more readilyavailable. The ll-ketobenzomorphans are readily available using thetetralone route (Scheme 6-1). Grignard conversion to the tertiary alcoholand subsequent dehydration yields the ll-methylene derivative (12)(Scheme 6-4). Catalytic hydrogenation under neutral cond.itions gives th~ aisomer (13) through addition across the {3face. ProtonattOn of the ammogroup in 12, however, causes the addition of hydrogen to occur from the aface of the molecule, resulting in formation of the ll{3-methyl group (14)in 70% yield (11). An alternative method involves the construction of a

256 6 The Beiizomorphans

Me Me

HeDcQrHe a,b ~e +~N

N+ + ~'II IMe Me C H Me6 5 C6HS

15 16

Me Me

~~e He\\+NC NC N

I IMe Me

C6HS C6HS

17 18

17

Me

~,,'He

~~Me

C6HS

19

Me

~,,'Me

;:.,~NC f IMe C6HS

~ 20

21Scheme 6-5. Reagents: (a) benzyl grignard; (b) perchloric acid; (c) sodium cyanide; (d)

hydrochloric acid. ether; (e) hydrochloric acid; (f) sodium borohydride; (g) aluminumchloride, carbon disulfide.

tetrahydropyridine containing substituents with defined stereochemistry(Scheme 6-5) (12). Addition of benzyl grignard to 1,3,4-trimethyl-pyridinium yields a mixture of iminium dienes 15 and 16, which can beseparated as their cyanide adducts 17 and 18. Reaction of the hydrochlo-ride salt of 17 with aqueous acid eliminates cyanide and results in therearranged iminium diene (19), with a trans relationship between thebenzyl and methyl groups. The diene (19) is trapped with cyanide for ease

L


Scheme 6-6.

of handling. For construction of the ,B-benzomorphan (21), the cyanide isreductively removed and the resultant tetrahydropyridine is cyclized withaluminum chloride in carbon disulfide. The cycIization catalyst and solventcombination had previously been used to enhance the amount of ,Bisomerformed in Grewe cyclizations (13).

A method for generating the tetrahydropyridine from a noncyclicprecursor is illustrated in Scheme 6-6. Conversion of the butenyl amine toits phenylacetamide allows cyclization to the dihydropyridine using theBischler-Napieralski reaction. Subsequent borohydride reduction thenyields the requisite Grewe tetrahydropyridine (14).

Novel methods for the construction of the benzomorphan frameworkhave included the use of homolytic chloramine cyclizations (Scheme 6-7)(15). The chloramine (22) is oxidized to the protonated aminyl radical,which cyclizes in 92% yield to a 4: 1 mixture of cis and trans piperidines(23). The cis compound readily undergoes a second intramolecular ringformation to yield the benzomorphan in 75% yield (16). A differentapproach uses the construction of the aromatic ring onto the existingaza-bicyclic framework (Scheme 6-8). By using standard methodology, theaza-bicyclic (24) is converted to 25, which contains a heterocyclic pyronering in place of the usual benzene ring in benzomorphans. The pyrone ringin 2S is sufficiently reactive to undergo an inverse electron demandDiels-Alder reaction with the electron-rich dienophile, dimethoxy-ethylene. The regiochemistry of the cycloaddition is such that a methoxyl

258

22

b--?

6 The Benzomorphans

23

Scheme 6-7. Reagents: (a) TiCI). aqueous acetic acid; (b) aluminum chloride.

24

b>

c,d

a--+

25

26 R = C02Et27 R = C02H

R = H

. Scheme 6-8. Reagents: (a) dimethyl methoxymethylenemalonate, base; (b)dlmethoxyethylene; (c) sodium hydroxide; (d) copper powder, quinoline, 22'C.

1,1-

l

III Structure-Activity Relationships in the Benzomorphan Analgesics 259

group is inserted in the appropriate 8-position of the resultant benzomor-phan (26) after decarboxylation and aromatization. The superfluous estergroup at C-9 is readily removed via 27 in 97% yield to give the 8-methoxybenzomorphan (17).

III. Structure-Activity Relationships in theBenzomorphan Analgesics

A. The Effect on Analgesia of Alkyl Groups in Rings Band C

The majority of the benzomorphan analgesics synthesized have substi-tuents at positions 6 and 11, the BC-ring junction and the Coring,respectively. These two positions correspond to the vestiges of the Coringin morphine, which includes the critical 14-position of morphine. Althoughit is generally felt that substitution at these two positions is necessary, it isinstructive to see how this supposition was developed. This section isrestricted to the N-methyl substituted benzomorphans. Other examples ofN-alkyl substitutions are found throughout this chapter.

Despite the diverse array of synthetic approaches to benzomorphansreported in Section II, the parent unsubstituted benzomorphan (32) hasbeen prepared by another method (Scheme 6-9). This reaction sequencestarts from the pyridinium salt (28), which is readily available from4-phenylpyridine, and has as its critical step the intramolecular Friedel-Crafts acylation of the 4-phenylpiperidine carboxylic acid (30). Theresultant I-keto compound (31) is easily converted to the parent benzo-morphan (32) (18). The corresponding 8-hydroxy (33), 8-acetoxy (34), and8-methoxy (35) derivatives, which are equivalent to the 3-position deriva-tives in morphine, heroin, and codeine, respectively, have been synthe-sized using standard Grewe methodology. In the mouse hot plate assay,the parent compound (32) has 10% of the activity of morphine, while the8-acetoxy derivative (34) has 16%. The methoxy substituted compound(35) is lethal at analgesic doses. The phenol (33) has 25% of the activity ofmorphine. This activity is of particular interest, since 33 lacks the quater-nary carbon atom, equivalent to C-14 in morphine, once thought essentialto morphinomimetic activity. Perhaps the most surprising and differentiat-ing observation made in this series, as opposed to that of the more complexmorphine and morphinan, is that the racemate of 35 appears to have opiateantagonist properties, causing abstinence symptoms in morphine-dependent monkeys at equianalgesic does (19).

In the monoalkyl substituted benzomorphans, the 6-position has beenmost intensively studied, followed by the 11a- and l1,B-substituents. The

260 6 The eenzomorphans

a,b~

28 29

f-30 31

32 (R = R)

33 (R = OH)

34 (R = 02CCH3)

35 (R = OCR3)Scheme 6-9. Reagents; (a) KCN; (b) methanol, hydrochloric acid; (c) methyl iodide; (d)

Hz/Pt; (e) hydrochloric acid; (f) polyphosphoric acid; (g) Wolff-Kishner reaction.

6-methyl A-ring unsubstituted compound was prepared early in thedevelopment of this type of molecule and has minimal hot plate activity(5). The effect of increasing alkyl substitution at position 6 in the8-hydroxybenzomorphans is illustrated in Table 6-1. The 6-methyl deriva-tive (36) is slightly less analgesic than the unsubstituted compound (33),but analgesic potency increases with chain length, with the peak atn-propyl, and then slowly diminishes. The total effect of chain length at thisposition on analgesia is not very strong.

A series of 6-phenyl benzomorphans has been prepared as part of alarger investigation that included the more interesting 6-phenyl-ll-methylcompounds. The presence of the aryl ring allows a variety of syntheticapproaches (25,26) to these biologically interesting molecules in addition

i


Table 6-1

The Effect of Increasing Alkyl Substituent Length at C-6 in

Monosubstituted Benzomorphans

HO

Compound R Analgesic ActivityU Reference

33363738394041

HCH)

CzHsn-C3H7n-C4H9n-CsH 11n-C6H13

0.25 /80.14 200.65 2/0.76 220.48 230.50 240.11 23

U Relative to morphine = I, hot plate assay.

to the standard Grewe synthesis (27). A versatile synthesis that allows thepreparation of five-, six-, and seven-membered C-rings is illustrated inScheme 6-10. The readily accessible tetralone ester (42) is converted toits amide (43). Subsequent bromination allows ri~g closure to the ketobenzomorphan lactam (44). Removal of the oxygen functions yields6-phenylbenzomorphan (45) (26). The 6-phenyl compounds are not veryactive analgesics (Table 6-2). The unsubstituted (45) and the 8-hydroxy(47) derivatives are equipotent, having about 20% of the activity of mor-phine. The presence of a para-chloro substituent on the 6-phenyl ring retainsthe analgesic properties, but a para-hydroxy group eliminates it (28).

The 1113-methyl benzomorphans have been prepared using a tetraloneroute similar to that shown in Scheme 6-10 (29). The same tetraloneapproach to the lla-methyl series yields only a naphthalene derivative. Amore circuitous route using intramolecular mercury(II)-induced cycliza-tion of an amino group to the double bond in a dihydronaphthalene yieldsthe lla-methyl analog (30). A subsequent synthesis allows stereospecificsynthesis of either epimer from a common intermediate (31). The unsubsti-tuted 1113-methyl (50) and its 8-hydroxy derivative (51) are comparable inanalgesic potency to codeine and morphine, respectively (32). Neithercompound supports morphine dependence in rhesus monkeys; (51) pre-cipitates withdrawal symptoms when substituted for morphine. This opiate

0II

~~-CII]

~"'

~H CONII(CII']

c d- --C6H5

6 544

0II

~-CH ~-CII]

o C6HS]~C6H5

~_CIICH3

o "'CH]]

R HO

50 (R H) 52

51 (R OH)

Compound R1 R2 Potency.

45 H H 0.1846 H CI Activeb

47 OH H 0.1848 OH Cl Activeb

49 OH OH

a Relative to morphine = 1, mousewrithing assay.

b Mouse tail flick assay.

262 6 The 'Benzomorphans

oII

~C02Et6 5

a-

42 43

45.Scheme 6-1~. Reagents: (a) NH2CH3; (b) bromine; (c) sodium methoxide; (d) Wolff-

Klshner reachon; (e) lithium aluminum hydride.

antagonistic activity is similar to that observed with the unsubstitutedcompound (33). The lla-isomer (52) has approximately 0.25 times the


Table 6-2

Analgesic Activity of

6-Phenylbenzomorphans

analgesic potency of the {3isomer (51), but again, it is not morphine-like inaddicted monkeys. Compound 52 also possesses antagonist properties andcauses long-lasting abstinence syndrome in monkeys (30).

During the conceptual development of the benzomorphan molecule,morphine was dissected by cleavage of the Coring, leaving the quaternarycarbon and the tertiary carbon at C-14 intact. The retention of thesefeatures, using substitution by methyl groups, was originally felt tocontribute to analgesic activity by providing steric bulk similar to that ofthe excised alicyclic Coring (2). A series of A-ring unsubstituted 6,11-dialkyl benzomorphans having both the a and {3 conformations is pre-sented in Table 6-3. Even in the absence of the phenolic 8-hydroxyl,substantial analgesic activity is retained. For instance, both the 6,11a and-{3diethyl substituted compounds 53 and 54 are approximately one-half aspotent as morphine (33). In this particular unsubstituted series, there islittle difference in potency has been observed between the 11a and {3stereoisomers, the maximum being a factor of 3 with 6, II-dimethylsubstitution.

The situation is remarkably different in the 8-hydroxy series (Table6-4), where up to an 80-fold difference in analgesic potency between the

@f$:"Jo '-, 1R

Compound R1{3

R2 Analgesic Potency" a References

9 CH] a-CH] 0.08 82] CH] {3-CH] 0.24 313,22

53 C2Hs a-C2Hs 0.42 3354 C2Hs {3,C2Hs 0.50 1.2

3355 n-C]H7 a-CH] 0.10 11.3456 n-C]H7 {3-CH] 0.25 2.5

lJ,34

" Relative to morphine = I. mouse hot plate assay.".

Table 6-4

6, II-Dialkyl Substituted 8-Hydroxybenzomorphans

~:"3o -, 1RHO

{3Compound R' R2 Analgesic Potency" a References

]] CH] a-CH1 0.7 2257 CH3 {3-CH3 4.8 16

22,3558 CH] a-~Hs 1.5 22.3659 CH3 {3-C2Hs 4.5 3

22,3660 CH3 a-n-C3H7 0.75 376] CH] {3-n-C]H7 1.7

2.337

62 C2Hs a-CH] 0.43 22,3863 C2Hs {3-CH] 30.0

7022.38

64 C2Hs a-C2Hs 0.50 381565 C2Hs {3-C2Hs 7.5 3866 n-C]H7 a-CH3 0.58 3767 n-C]H7 {3-CH] 10.0 17

3768 n-C]H7 a-n-C]H7 0.03 2269 n-C]H7 {3-n-C]H7 2.4 80

22

" Relative to morphine = I, mouse hot plate assay.

~N-,"IIIR23

o ;;;1

R

HO

AnalgesicCompound R1 R2 Enantiomer Potency. PDLb

II CH] CH] Leva 2.0 NoneCH] CH] Dextro Inactive None

60 CH] IJ-C]H7 Leva 1.1 NoneCH] n-C]H7 Dextro Inactive None

64 ~Hs ~Hs Leva 1.0 None

~Hs ~Hs Dextro 0.16 Intermediate

66 n-C]H7 CH] Levo 1.5 Nonen-C]H7 CH] Dextra 0.1 High

36 CH] H Levo 0.67 NoneCH] H Dextra 0.05 Low

37 ~Hs H Leva 2.0 None

C2Hs H Dextra 0.06 Low

Table 6-3

Analgesic Activity of 6, II-Disubstituted Benzomorphans .without A-Ring SubstitutionIII Structure-Activity Relationships in the Benzomorphan Analgesics 265

stereoisomers is observed. This significantly increased analgesic activity is ageneral rule with 8-hydroxy substitution (39). On the basis of the limitednumber of substituents contained in Table 6-4, the optimum substitution atC-6 appears to be ethyl, while at C-lI a J3-methyl group is best (2,37). Theresultant benzomorphan (63) is 30 times more potent than morphine.Compound 11, metazocine, is considered the parent of the entire series ofdialkyl benzomorphans. The compounds contained in Table 6-4 all showmoderate to strong analgesia in the mouse and low or no physicaldependence liability in rhesus monkeys, a clear separation of morphineeffects.

The monoalkyl and dialkyl benzomorphans listed in Tables 6-1 and 6-4are all racemates, since they have been prepared by total synthesis fromoptically inactive precursors. Separation of the enantiomers has beenachieved using classical resolution techniques, and a comparison of thebiological activities is given in Table 6-5. As expected, the levo enantio-mers are twice as potent as the corresponding racemates and, like the

Table 6.5

Pharmacological Properties of 6- and 6,1l-Alkyl-8-hydroxybenzomorphan Enantiomers

.Relative to morphine = I, mouse hot plate assay.b Physical dependence liability.C Relative to nalorphine = I.

MorphineAntagonismC

0.02-0.03NoneYesNone0.1None0.2None0.02None0.02-0.05None

C'o (1CH)

/'CH) +

~~II

CH) CH)

72 7)


racemates, do not sustain morphine dependence in rhesus monkeys (this ischaracteristic of no physical dependence liability). They actually demons-trate a nalorphine-like opiate antagonism in causing the morphine absti-nence syndrome in addicted monkeys. The most effective is the levo isomerof the 6-propyl-11a-methyl derivative (66), which is one-fifth as potent asnalorphine as an antagonist but is a more potent analgesic than morphine.Just as surprising is the capacity of the majority of the dextro enantiomersto substitute for morphine (40). The 6-methyl-1l13-propyl racemate (61)has also been resolved into its enantiomers. As expected, the levoenantiomer of 61 is considerably more potent than morphine and exacer-bates the morphine withdrawal syndrome in addicted rhesus monkeys,indicating that it too possesses opiate antagonist properties. The dextroenantiomer of 61 lacks opiate activity (41).

The 6-phenyl-ll-alkyl benzomorphans have been prepared as an out-growth of the I1-desalkyl derivatives (d. Table 6-2). In contrast to thesesimpler derivatives, the II-alkyl derivatives arise from a completelydifferent synthetic approach, as illustrated in Scheme 6-11 (42). Thetertiary alcohol (72) is readily prepared by grignard addition to 1,3-dimethylpiperidone. Acid-catalyzed dehydration yields an equimolar mix-ture of the two isomeric tetrahydropyridines 73 and 74. After extendedacid treatment, 74 becomes the predominant isomer (73:74 = 15:85).After quaternization of 74 with p-methoxybenzylbromide, Stevens rear-rangement affords the necessary Grewe intermediate (75), which cyclizesexclusively to the 1113-methyl derivative (71) (42). The exclusive forma-tion of the 1113-isomer is unusual and has been rationalized in terms ofdifferential stabilities of the phenyl-stabilized carbonium ions in the Grewecyclization (2,42). The l3-conformation in 71 was ultimately confirmed byX-ray structural analysis (43).

The biological activity of a series of 6-phenyl-l1-alkyl benzomorphans,including the enantiomers of 71, is presented in Table 6-6. Of thesecompounds, the most extensively studied is 71 and its enantiomers (44).Levo-7I is not only a potent analgesic but also an effective opiateantagonist, precipitating withdrawal symptoms in addicted monkeys (45).The antagonistic potency has been compared to that of nalorphine.Morphine antagonism could even be demonstrated in the mouse tail flickanalgesia assay. The dextro enantiomer of 71 is not only an analgesic butalso possesses a high level of physical dependence liability and causescomplete suppression of morphine withdrawal symptoms in monkeys at 5mpk (45).

Clinically, metazocine [( - )-ll] and G PA 1657 [( - )-71] have beenstudied. In humans, metazocine [(-)-ll] is an excellent pain reliever, butwith respect to abuse potential it is similar to morphine rather than


74

c-

75

HO @71

Scheme 6-11. Reagents: (a) hydrochloric acid, heat, 15.minutes; (b) hydrochlor.ic ac.id.48-hour reflux; (c) anisyl bromide; (d) KOH. toluene, 108 C; (e) 48% hydrobromIc aCid.

nalorphine. The correspondence between animal and human tests has beenat best qualitative and thus disappointing (46). In humans, GPA 1657[(-)-71] is a potent analgesic, both orally and parenterally. Orally, G.p~1657 is 20 times as potent as pentazocine (see below), and parenterally It IStwice as potent as morphine. In spite of its antagonistic properties: GP A1657 causes most of the usual morphinomimetic side effects: respiratorydepression, dizziness, nausea, and euphoria. Interestingly, in a singleuncontrolled study, tolerance was not obs,erved after 90 ~ay.s.of t.reatment.There was also no evidence of physical dependence hablltty In a largepatient study, which is consistent with its antagonist properties (45).

AnalgesicCompound R1 R2 R3 Potency" Reference

70 H H CH3 A 28(:t )-71 OH H CH3 2.4 42( - )-71 OH H CH3 6.7 42( + )-71 OH H CH3 0.4 42

76 OH CI CH3 A 2877 OH F CH3 A 2878 OH H ~H5 A 28

"Relative to morphine = I, mouse hot plate assay,

Compound R Analgesic Potency"

81 CH3 0.0782 ~H5 0.1683 n-C3H7 0.2184 n-C4H9 0.2285 C(CH3h Inactive


Table 6-6

Analgesic Activity of 6-Aryl-II,B-alkylbenzomorphans

A hybrid of the benzomorphan system with portions of the extremelypotent thebaine Diels-Alder adducts is exemplified by structures 79 and80. The unique tertiary carbinol function found at position 7 in theDiels-Alder adducts has been similarly positioned at llJ3 in the benzo-morphans. Despite their lack of a phenolic group at position 8, theseanalogs, 79 and 80, possess 40% of the analgesic activity of morphine; thisis somewhat disappointing in view of the 400-fold increase seen in theDiels-Alder adducts (47). A series of analogs of 80 has been reportedthat are 6-methyl-8-hydroxy derivatives in which the length of the aliphatictail beyond the tertiary alcohol has beeen varied (48), Despite the phenolichydroxyl, all of these compounds are less active as analgesics than 80(Table 6-7), and they do not demonstrate any opiate antagonism.

Other disubstituted benzomorphans are the 8-methoxy-I, I-dimethylderivative (86), which is about twice as potent as codeine (49), and the5,6-dialkyl compounds. Apart from the 6,lla- and -J3-derivatives, the5,6-dialkylbenzomorphans are obtained in vanishingly small yield inthe Grewe cyc1ization (50). The 5,6-dimethyl derivative (87) possessestwo-tenths the activity of metazocine (11), while the 5-methyl-6-ethyl-88has only 0.05 times the analgesic activity (50).

111 Structure-Activity Relationships in the Benzomorphan Analgesics 269

Table 6-7

a Relativetometazocine(lI) = l,mouseacetyl-choline writhing assay.

79 (R = COCH 3)

80 (R = C(CH3)20H)

86 87 (R = CH3)

88 (R = C2HS)

Many potential combinations for three substituents in the BC-rings ofbenzomorphan exist, but relatively few have been studied. Both a methylgroup and a phenyl ring have been introduced into the I-position ofmetazocine via the I-ketone. Neither of these derivatives, 89 or 90, hassignificant analgesi,c potency (51).

HO

89 (R = CH3)

90 (R = C6HS)


4 steps,

91

Scheme 6-12. Reagents: (a) methyl grignard; (b) hydrobromic acid.

A much more interesting group of trisubstituted benzomorphans is the6,11,11-trialkyl compounds, which, with varying nitrogen substitution, hasled to interesting and specific opiate receptor ligands. In the N-methylderivatives, the pharmacological profile is similar to that of the 6,11-disubstituted derivatives, but the trisubstituted compounds are morepotent and much longer-acting (52). The construction of trimethyl deriva-tive 91 is briefly outlined in Scheme 6-12. The major synthetic challenge isthe construction of a 2-benzyl-1,3,3,4-tetralkylpiperidine-4-ol that under-goes a Grewe-type cycJization on acid-catalyzed carbonium ion formationat C-4 (52). The compounds prepared in this way are presented in Table6-8. The majority are 11,11-dimethyl derivatives, the most active being the6-ethyl (92) and 6-phenyl (94) derivatives, which have over 60 times theanalgesic potency of pentazocine (53). Acetylation of the 8-hydroxylincreases this activity fourfold. With the exception of the 11,11-tetramethylene (95), which has 12% of the antagonist activity of nalor-phine, none of these compounds possess opiate antagonist activity. Whilet~ere is a paucity of opiate receptor affinity data, the 6-ethyl-11,1l-dImethyl (92) has significantly higher receptor affinity than morphine (54).The X-ray crystal structure of gemazocine (91) has been determined (55).In summary, the advantage of the 1l,11-disubstitition over the ll-mono-


Table 6-8

Analgesic Potency of 6,11,11- Trisubstituted Benzomorphans

CompoundAnalgesicPotency.

OpiateReceptorAffinityb

91929394959697

CH)CH)CH)CH)(CH2).CH3CH3

CH3~H5n-C3H7C6H5~H5~H5C2H5

HHHHHCOCH3CH3

12.562.54262.516'

25016 0.07

a Relative to pentazocine (150) = I, rat tail flick assay.b Relative to morphine = 1, IC50 = 3.4 nm.,

Antagonist activity = 0.12 relative to nalorphine = 1.

substituted benzomorphans is its greater potency and much greater dura-tion of action (52).

The incorporation of the tertiary hydroxyl side chain in the oripavine-based analgesics, originally described for the 6-methyl benzomorphans,has been extended to the 6,lla-dimethyl derivatives (48,56). The polar-ization of activity in these compounds, either agonist or antagonist, isillustrated in Table 6-9. The antagonistic potency of N-methyl (100) is fivetimes that of nalorphine, making it among the most potent 3-methylantagonists known (56). The replacement of the tertiary alcohol by asecondary ketone in these derivatives has been undertaken to prepareanalgesics with better agonist-antagonist properties (57). Noteworthy inthese benzomorphan ketones (Table 6-10) is the increase in analgesicpotency as the linear aliphatic chain of the ketone is extended from 101 to104. The activity peaks at 104, which has 35 times the potency of morphinein the writhing assay and 100 times that in the tail flick assay. Analgesicactivity then falls off rapidly as the chain length is further extended. Thesmaller straight chain analogs, in contrast to the tertiary alcohols (98-100)do not possess opiate antagonist properties. However, the pentyl deriva-tive (105) retains some analgesic properties and is equivalent to naloxone

AntagonistCompound R Writhing Tail Flick Activityb

101 CH3 2.4 1.6 Inactive102 CzHs 3.3 3.9 Inactive103 C3H7 26 39 Inactive104 C4H9 35 100 Inactive105 CsHlI 2.5 Inactive 1.0106 C6HI3 0.05 Inactive 0.2107 i-C3H7 5.5 0.2 Inactive108 i-C4H9 32 58 Inactive109 i-CsHll 8.1 Inactive 0.03110 i-C6H13 0.1 Inactive Inactive111 (CHzhC6Hs 0.07 Inactive 0.5112 (CHzh-c-CsH9 0.02 Inactive 0.7

Q

Relative to morphine = 1.b Relative to naloxone = 1.

Table 6.9

Benzomorphan Alcohol Derivatives of the Oripavines

CompoundAnalgesicPotency.

AntagonistActivitybR

9899

100

CH3C(CH3h(CHzhCH(CH3h

0.2<0.02<0.02

0.040.305.0

" Relative to morphine = 1.b Relative to nalorphine = 1.

Table 6-10

Benzomorphan Ketone Derivatives of the Oripavines

Analgesic Potency"


as an antagonist. When the ketone side chain is branched, the analgesiceffects in the writhing assay are reduced, and in the tail flick assay they areeliminated for all the derivatives except 108, which is still a very potentanalgesic. The derivative 112 appears to be a potent antagonist with noagonist effects, since the reported analgesic activity of 112 is non-enantioselective (58). The receptor affinities of 112 are interesting. Initially, 112was postulated as a selective K antagonist; however, subsequently, it wasdemonstrated that 112 has a receptor selectivity similar to naloxone at the

,.", 8, and K receptors (59). In addition, compared again to naloxone, itsduration of action is substantially longer (59).

The introduction of three alkyl groups at positions 6 and 11 has thus ledto potent analgesics and antagonists with either relatively simple functionalgroups like gemazocine (91) or with the more complex oripavine portionsjust discussed.

B. Nitrogen Substitution

The effect of substituents in the Coring on induction of opiate antagonistactivity in the N-substituted benzomorphans has been noted several times.The effect of substitution at position 3, the amino group, is therefore morecomplex than in either the morphine or morphinan series, because not onlydoes the amino substitution have to be considered for mixed agonist-antagonist activity, but the pattern of substitution in the other portions ofthe benzomorphan ring system must be considered as well. This section onnitrogen substitution consists of three subsections: N-alkyl substitution,unsaturated and cycloalkylalkyl substitutions, and furan and related substi-tuents. Of the three, the second has been, by far, the most extensivelyinvestigated.

1. N-Alkyl Substitution at Nitrogen The investigation of the effect ofN-alkyl chain length on analgesic activity in the 6,11a-benzomorphanswas one of the earliest structure-activity studies undertaken in the benzo-morphans (Table 6-11). (60). The 3-ethyl (114), 3-n-propyl (115), and3-n-butyl (116) derivatives are devoid of analgesic activity, but the3-n-pentyl homolog is as active as morphine. This activity parallels almostexactly that seen in the morphine series. Initially, the n-propyl derivative(115) was not investigated for antagonist activity. However, when thepotent antagonist activity of n-propylnormorphine became known, n-propylbenzomorphan (115) was reinvestigated; it proved to be a stronganalgesic antagonist, even surpassing the N-allyl compound (144) (61). Theinfluence of epimeric II-methyl groups has been studied in the 3-propylbenzomorphans. For agonist, the ll-trans compounds generallyhave greater agonist activity than the cis compounds. The difference is less

Analgesic AntagonistCompound R1 R2 Potency" Activityb

119 ~Hs H Inactive Inactive120 ~Hs CH3 1.2 Inactive121 C2Hs ~Hs Inactive 0.5122 C2Hs /I-C3H7 Inactive 3.7123 ~Hs /I-C4H9 0.02 1.1124 C2Hs rr-CSHII 0.13 Inactive125 C2Hs fI-C6HI3 0.04 Inactive126 ~Hs rr-~H1s 0.03 Inactive

o/WI 127 ~Hs rr-CgH t7 0.02 Inactive~128 /I-C3H7 CH3 0.44~ ",o..w-1 :.

(129 fI-C3H7 ~Hs -d

130 fI-C3H7 /I-C3H7 Inactive Active131 ll-C3H7 n-C6H13 0.1 Active

274 6 The "Benzomorphans

Table 6-11

The Effect of N-AlkyI Length on NormetazocineBiological Activity

CompoundAnalgesicPotency"

AntagonistActivitybR

113114115116117118

CH3~HsfI-C3H7rr-C.Hg/I-CsHIl/I-C3H7II,B

0.7InactiveInactiveInactive1.0Inactive

7.0

2.4

" Relative to morphine = I.b Relative to nalorphine = I.

pronounced for antagonists. Indeed, the 11,B-methyl derivative (118) hasonly 35% of the opiate antagonist activity of its I la-methyl epimer (62).

A similar study of alkyl chain length effects on nitrogen has beendescribed for benzomorphans with 6-methyl and both II-ethyl and 11-propyl substituents. The lla-ethyl series parallels the lla-methyl com-pounds, with the ethyl (121), propyl (122), and butyl (123) derivativeshaving weak or nonexistent analgesic properties but being rather potentantagonists (Table 6-12). Analgesic activity is restored with the n-pentylderivative (124) and then slowly decreases as chain length increases (63).With the 1Ia-n-propyl substitution, the results are different, an example ofthe complexity inherent in the benzomorphans. The effect of N-substitution with 6-methyl-lla-n-propyl substitution does not follow thestructure-activity relationship established in the preceding benzomor-phans, the morphinans, or the morphine derivatives. Analgesic potencydrops substantially as expected in the ethyl (129) and is eliminated in the3-n-propyl (130), but is not restored with n-pentyl or n-hexyl (131)substitution; all the derivatives from ethyl (129) through n-hexyl (131)have narcotic antagonist properties. Higher homologs are inactive. As thelength of the alkyl chain increases, so does the duration of antagonisticactivity. The ethyl derivative (129) has a moderate duration of activity,


Table 6-12

Thc Effect of II-Alkyl Substitution and N-Alkyl Length on BenzomorphanAnalgesic Activity

OpiateReceptorAffinity

U Relative to morphine = I, mouse writhing assay.b Relative to nalorpine = I.C Nanomolar.d Poor dose response.

while the n-propyl (130) has a very long duration. Other higher homologsare less potent than nalorphine but are faster-acting and of longerduration. The n-hexyl derivative (131) is somewhat different; its onset ofactivity is slower, but it possesses a very long duration of activity (64).

Halogenated alkyl substituents on nitrogen have been synthesized for avariety of reasons. The first attempt was aimed at irreversible receptorlabeling using 2-bromoethyl derivatives of normetazocine. The premisewas based on the formation of covalent bonds with anionic receptorbinding sites. Although the bromoethyl derivative was a more effectiveanalgesic than the corresponding 2-hydroxyethyl derivatives, the signi-ficance of this effect could not be assessed, since the bromo derivatives hada sustained depressant action not observed in the hydroxyethyl compounds(65). A series of 2-fluoroethyl substituted normetazocines has been

RelativeCompound R Analgesic Potencya Affinityb

114 H] 0.03 180132 HzF 0.13 50133 HFz 0.12 1Ooo134 F) Inactive. 1700

toxic

N-(CH2)nR1

"'R3

H

AnalgesicCompound II RI R2 R) potencya Reference

137 2 C6HS CH] CH] 4.8 69138 2 C6Hs CzHs CzHs 0.6 38139 2 C6HS 1I-~H7 CH] 1.3 70140 2 COC6HS CH) CH) 0.5 7/141 3 C6HS CH) CH) 0.1 72142 2 C6H4-p-NH2 CH) CH) 11 72143 2 C6H4-p-OCH) CH) CH) 3.8 72

a Relative to morphine = 1.


Table 6-13

2-Fluoroethyl Substituted Normetazocines

a Relative to morphine = I, mouse writhing assay.b Receptor affinities in nanomolar.

prepared to test the effect of amine basicity on analgesic potency (66). Themonofluoroethyl derrivative (132) is a more potent agonist than the almostinactive N-ethyl derivative (Table 6-13), and analgesia falls off as thedegree of fluorination increased. The most active member of this series(132) has exceptional toxicity due to metabolic N-dealkylation and subse-quent conversion of the fluoroethyl group to fluoroacetate, which is asuicide substrate for the Krebs tricarboxylic acid cycle (66). As withfluorinated side chains, an interesting hybrid between benzomorphans andthe major tranquilizer butyrophenones has been synthesized. The resultantcompound (135) is a potent analgesic (with 3.5 times the potency ofpentazocine) with a significant amount of central nervous system (CNS)depressant activity (67).

An interesting substituent is the w-cyanoalkyl group, which leads tocompounds whose analgesic potency has a very strong dependence on thealkyl chain length (68). The most potent is the cyanoethylene derivative(136), which is 30 times as potent as morphine and does not substitute for

135 136


Table 6-14

3-Aralalkyl Benzomorphans

morphine in drug-dependent rhesus monkeys. It is worth comparing 136with the N-propyl derivative liS, which is a very potent antagonist withoutanalgesic properties.

A series of aralalkyl substitutions on normetazocine yields some potentanalgesics, one of which is clinically useful (Table 6-14). Introduction of aphenethyl side chain yields a potent analgesic, phenazocine (137), which isfive times as potent as morphine. Variation of the alkyl length at positions6 and 11 (e.g., 138 and 139 decreases this activity, as does increasing thechain length (141) or introducing a keto-group (140). Substitution onthe aromatic group, 142 and 143, retains analgesia. Phenazocine (137)is a clinically useful compound, although no longer marketed (73). Itis an effective analgesic parenterally for most types of severe pain andorally for chronic pain. Tolerance develops more slowly to phenazocinethan to morphine, and it appears to have less physical dependenceliability (73).

2. Unsaturated Alkyl and (Cycloalkyl) alkyl Substituents on Ni-trogen It is well known from the work on the morphine and morphinanseries that the change from an N-methyl group in compounds that areopiate agonists to allyl, cyclopropylmethyl, or similar groups usually resultsin analogs that possess opiate antagonist activity. In the benzomorphans,antagonist activity in N-methyl substituted derivatives has been observedfor the first time. It was therefore to be expected ttiat the substitutionof the N -methyl group in metazocine by the usual antagonist functions

278.

6 The Benzomorphans

Table 6-15

Unsaturated Alkyl 3-Substituted Benzomorphans

Compound R

144 CH2CH- CH2(SKF-1O,047)

145 CH20=CH146 CH2CH=CCI2147 CH2CH=CHCI148 CH2CCI=CH2149 CH2CCH3=CH2150 CH2CH=C(CH3h

(pentazocine)

AnalgesicPotency"

AntagonistActivityh

1.9

ooooo<0.1

0.10.025.60.021.00.02

a Relative to morphine = 1.b

Relative to nalorphine = I.

would lead to interesting biological effects. This expectation has beenrealized as the generic opiate receptor has been subdivided into severaltypes, primarily on the basis of results obtained with various benzomor-phans.

A series of substituted and unsubstituted N-allyl and propargyl deriva-tives of normetazocine is presented in Table 6-15. As can be readily seen,the allyl substitution (144) generates a potent antagonist without analgesicproperties (74). Opiate antagonism is significantly reduced in the propargylanalog 145 as well as in the halogenated allyl groups 146 and 148.However, the 3-chloroallyl (147) and 2-methylallyl (149) substitutionsretain potent antagonist properties (74). Probably the most importantclinically useful compound in this series is the 3,3-dimethylallyl derivative(150), pentazocine (74). Pentazocine (150) is a weak analgesic antagonist,being only 1/50th as active as nalorphine in reversing the analgesic effect ofmorphine and phenazocine (137) (75). In humans, however, it is aneffective analgesic for a wide variety of painful stimuli. Parenterally, 150has one-third the activity of morphine, while orally it approximatescodeine's potency. Pentazocine has a relatively rapid onset of action with aduration of 3-4 hours (76). Pentazocine has a low physical dependence


liability (77) and is therefore not covered by the Harrison Narcotic Act.However, psychotomimetic effects have been noted (78).

Historically, the first subdivision of the opiate receptor into J..L,K, and atypes was made o~ the ba.sis of animal behavior studies (79). The litany ofsubtypes has continued with D(80), A (81), and € and further division of J..Linto J..L-land J..L-2(82). In particular, K and a opiates were shown to produceeffects through mechanisms that must involve receptors distinct from theclassic~l morp?ine J..Lreceptor. The K receptor ligands fail to suppressmorphine abstmence and do not cause abstinence in morphine-dependentmonkeys. They are also involved in diuresis and feeding behavior. The areceptor ligands mediate mania and psychomimetic effects (83). Thisreceptor is e~t~er identical to or very strongly coupled allosterically withthe phencyclidine receptor (84). The prototypic ligand for the a opiatereceptor is N-allylnormetazocine, SKF-10047 (144) (79). Compound 144causes mydriasis, tachypnea, tachycardia, hallucinations, and mania,effects considered to be mediated by the a opiate receptor. In rats andmice, 144 does not demonstrate analgesia in either the hot plate or tail flickassays. However, in the mouse writhing assay, N-allylnormetazocine isapproximately one-half as potent as morphine and the analgesia is reversedby naloxone (85). As expected, the analgesic activity resides in thelevoenantiomer (86). The affinities of 144 for various receptor subtypeshave been determined (87). Compound 144 has high affinity for both the J..L(0.4 nm) and D (0.6 nm) receptors, where it acts as an antagonist and anagonist, respectively (87). The affinity of 144 for the a receptor (7 nm) issignificantly less than that of the J..Lor Dopiate receptor (85,88). This is arather common OCCurrence where benzomorphans have relatively highaffinities for several types of opiate receptors.

Substitution on nitrogen with cycloalkyl groups, primarily with amethylene spacer between the nitrogen and the cycloalkyl function, hasproduced a highly interesting series of compounds. The 3-cyclopropylmethylene derivative (151), cyclazocine, is a potent opiateantagonist that also possesses central muscle relaxant and tranquilizingproperties in animal tests (Table 6-16) (74). Cyclazocine (151) has agonistproperties in animals and is an effective analgesic in humans, being 40times as potent as morphine (89). Although it produces addiction, thewithdrawal syndrome in addicts is not as severe as that experienced withmorphine (90). However, while cyclazocine is a very effective anaglesic inhumans, it produces too high a level of psychotomimetic effects to beclinically useful (91). The cyclobutylmethyl derivative (152) is similar tocyclazocine (151) but has weaker muscle relaxant properties and isequivalentrto pentazocine (150) in rodent analgesic tests. In addition, 152is an opiate antagonist of intermediate potency, being about one-fifth as

Analgesic AntagonistCompound R PotencyO Activityb

151 CHz-c-C3H5 0.07 4.3(cyclazocine)

152 CHz-c-C.H7 0.11 0.22153 CH2-c-C5H9 0 0.29154 CHZ-C-C6HII 0 0.006155 (CH2h-c-C3Hs 0 0.88156 c-C5H9 0 0.54

157 -0 0 0.03

158 -Cl'lc(J 0 0.48


Table 6-16

Analgesic Activity of 3-Cycloalkyl Substitution inBenzomorphans

~N-R

_"'CH3o ~CH

3

HO

° Rclative to morphine = I, mouse tail flick assay.b Relative to nalorphine = I.

active as nalorphine (Table 6-16). The cyclobutylmethyl derivative (152)has also been investigated in humans, but it produces such intensepsychotomimetic effects that its analgesic properties cannot be accuratelyassessed (92). The cyclopentylmethyl derivative (153) is still a potentantagonist, but, it has no agonist activity and lessened tranquilizingproperties. Increasing the ring size to six carbons (154) causes a markeddiminution of antagonist properties and elimination of the other prop-erties. Increasing or decreasing the number of methylene groups betweenthe nitrogen and the cycloalkyl groups generally reduces all the biologicalproperties when compared to the cycloalkymethyl compounds.

All of the compounds hitherto discussed are racemates. In cases whereoptical resolution has been carried out, the major portion of the antagonis-tic activity has been found in the levo-enantiomer. With pentazocine (150),the levo-enantiomer is 20 times as potent as the dextro, while the ratio forcyclazocine (151) is 500 (93,94). In contrast, when the ll-stereoisomers of


pentazocine and cyclazocine are compared to the parents, there is virtuallyno difference in their biological properties (93). This is in contrast to themore striking differences seen in the metazocine analogs (d. Table 6-4).

The O-methyl ether of cyclazocine (159) is more potent than pentazo-cine in rodent analgesic tests and, as expected, less potent than cyclazocineas an antagonist (95). A limited clinical trial with 159 was stopped afterthe usual side effects of cyclazocine appeared in an unusual time course(96). Psychotomimetic side effects did not appear until 4-12 hours afterintramuscular administration and lasted for 2 to 31 hours. The reactionsvaried from emotional withdrawal, apathy, dysphoria, and communicationdifficulties to delusions, disorientation, spatial disorientation, and hallu-cinations (96).

159

The alkyl substituents at positions 6 and 11 have been varied todetermine the structure-activity relationships for opiate antagonism prop-erties (Table 6-17). Significant enhancement of opiate antagonist prop-erties over those of the parent 6,1l-dimethyl derivatives is seen with apropyl group at C-6 or an ethyl group at C-lI (62). A variety of6-phenyl-ll j3-methyl benzomorphans with 3-antagonist substituents hasalso been shown to have antagonist properties with slight to no analgesicproperties (28,45).

Stereospecific opiate receptor binding has been observed with thebenzomorphans using a brain homogenate (Table 6-18) (97). The pharma-cological relevance of this affinity is supported inter alia by its ability topredict analgesic and antagonist potencies, as measured by other standardin vitro assays (98). As demonstrated in Table 6-18, all the pharmacologi-cally active benzomorphans bind to the non differentiated brain opiatereceptor in the morphine range.

Besides the usual 6,1I-disubstitution patterns found in benzomorphanswith nitrogen antagonist substituents, a limited number of examples withsubstitution at C-5 have been reported (Table 6-19). When disubstitution isrestricted to positions 5 and 6, comparison of the SKF-10047 analogs 165and 166 with pentazocine (150) and its 5,6-positional isomer (167) showsapproximate equivalence in opiate antagonism (62). Inclusion of an

HO

AntagonistCompound R' R' R' Potency"

144 CH,CH~CH, CH, CH, 2.4160 CH,CH=CH, CzlIs CH1 2.3161 CH,CH=CH, n-C3H7 CH, 10.2150 CH,CH=C(CII,), CH, CH, 0.03162 CII,CH=C(CH,), CzHs CII, 0.01151 CH,-<J CH, CH) 4.3163 CH,-<J C,H, CII, 2.3164 CH,-<J CH) CzHs 22.4

a Relative to nalorphine = 1.

Table 6-18

Opiate Receptor Affinities for Benzomorphans

N _R1

IIJR3

<Qr\2HO'

Compound R' R' R' ICsu(nm)

(-)-11 CII, CH, CH, 30(+)-11 CII, CH, CH, >1000(-)-62 CII, C,II, CII, 14(-)-144 CH,-CII=CH, CH, CH, 2(-)-137 C,H,(CII,) CH, CH, 0.6(-)-151 CHz-c-CjHs CH, CH, 0.9(ot)-150 CH,-CH~C(CH,), CH, CH, 15

Morphine 3

IItCH)

\;:d/\2HO

AntagonistCompound R, R, R, Potency"

165 CII,CH=CH, CzHs H 3.5166 CH,CII~CH, CzHs CH, 3.0150 CH,CH~C(CII,), CH, II 0.11167 CH2CH~C(CII,), CH, CII, 0.04151 CH,-<J CH, H 4.3

168 CH,-<J CH, CH, <0.001

<l Relative to morphine = 1.


Table 6-17

The Effect of 6- and ll-Substituents on Opiate Antagonism Properties


Table 6-19

The Effect of Alkyl Substitution at Position 5 on Antagonist Properties

additional methyl group at C-5, on the other hand, completely eliminatesantagonist activity in the cyclazocine analog (168) (99).

A series of 6,ll,ll-trisubstituted benzomorphans containing a variety of3-substituents has led to compounds with surprising biological properties(52). These compounds, spanning a range of mixed agonist-antagonist andantagonist substituents, not only possess strong opiate antagonistic prop-erties compared to nalorphine but are also active as agonists in the tail flickassay, where most benzomorphans show up weakly, if at all (Table 6-20)(53).

One of the more interesting compounds to come out of this trisubstitutedseries is bremazocine (177), which contains the unusual hydroxycyclo-propyl methyl group on nitrogen (100). Bremazocine (177) appears to be apotent and long-acting K receptor agonist (100) that also exhibits some I-'receptor antagonist properties (101). Compound 177 is a potent, centrallyacting analgesic with a long duration of action, being three to four times aspotent as morphine in the tail flick and hot plate assays. However, in themonkey shock titration test, 179 is 180-fold more active than morphine.Bremazocine is free of physical and psychological dependence liability anddoes not produce respiratory depression (100). On the basis of its

284

Table 6-20

Agonist and Antagonist Properties of

6-Substituted-l1,11-dimethylbenzomorphans

HO

.6 The Benzomorphans

Compound R IR'

AnalgesicPotency"

AnalgesicActivityb

169 CH,CH~CH,170 CH,CH=CH,171 CH,C=CH172 CH,CH~C(CH3),173 CH,CH=C(CH3),174 CH;!.c-C3H5175 CHrc-C3Hs176 CH2-c-C4H1

CH3C,H,C,H,CH3C,H,CH,C,H,C,H,

2.0<2<0.5

2.016

4.0<2.016

15.57.83.9

<2.0<2.015.5317.8

a Relative to pentazocine = 1, rat tail flick assay.b Relative to nalorphine = 1.

177 (bremazocine)178IR=CH3)

179 (R = CICH3)3)

pharmacological profile, bremazocine shows a promise of becoming aprototypic K receptor ligand (100).

.A series of 6,11,11-trisubstituted compounds has been reported that

m~orporates the tertiary alcohol side chain at position 7 of the oripavineDlels-:Alder adduct buprenorphine (48,56). The benzomorphan bupre-norphme analogs 178 and 179, while more potent as opiate antagoniststhan buprenorphine, possess only a small fraction of the analgesic prop-erties of the oripavines (48,56).


3. Heterocyclic Substituents on Nitrogen The interest in heterocyclicsubstitution on nitrogen in the benzomorphans originated with observa-tions in the morphine and morphinan analgesic studies, where substitutionof the methyl group by phenethyl and subsequently thienylethyl led tosignificant enhancement of analgesic potency. This area of study evolvedwhen it was realized that some heterocycles bear a resemblance to theopiate antagonisl allylic group. For instance, a furylmethyl group's 11'-electrons and oxygen lone pair are delocalized over the furan ring to forman aromatic system. However, the furan ring does exhibit residual olefinicproperties and would be expected to resemble an allyl group (102).

The thienylethyl substitution at position 3 forms a potent analgesic (180)when compared to either morphine or metazocine (72). Replacement witha furylelhyl (183) results in an analgesic 25 times as potent as morphine andwithout antagonist properties (Table 6-21) (103). Both 180 and 183function as typical morphine-like JL-agonists because the heterocyclicolefinic contribution is an additional methylene group removed from theallylic posilion.

In contrast to the thienylethyl derivative (180), the thienylmethylcompound (181) is not an analgesic and possesses some opiate antagonistproperties (104). Replacement of the sulfur with oxygen yields thea-furylmethyl compound 182, which does have slight analgesic activity butis as potent as nalorphine as an antagonist (105). The correspondingf3-furylmethyl derivative 184 retains the antagonistic activity while losingthe analgesic effects. More interesting are the methyl-substituted furyl-methyl derivatives 185 and 186 (104,106,107). The derivative 186 is amixed agonist-antagonist analgesic, while its positional isomer (185) is apotent agonist without antagonist properties. However, 185 does not exertthe typical morphine-like side effects, including physical dependenceliability. The furylmethyl analogs, particularly 185, display a selectivitytoward K opiate receptors (108). The original premise that an appropriateheterocyclic methyl group can produce either mixed agonist-antagonist orantagonist properties seems to be established.

A detailed structure-activity investigation has been conducted in thefurylmethyl series (182, 184-186). In the 6-substituted compounds, in-creasing the 6-substituent from hydrogen through n-propyl results in smallqualitative changes in either analgesic or antagonistic properties or both(104). Similarly, the difference in activity between the 11a- and 1113-epimers of compounds 182 and 184-186 is small. The most striking effect isthe sixfold decrease in analgesic activity on going from the a to the 13conformation in both 185 and 186 (104). Variouscombinationsof methyland ethyl substitution patterns at posilions 6 and 11 have resulted in littlechange in comparison to the respective parents (104).

Analgesic AntagonistCompound R POlencya Activityh

180 -(CH'h-Z) 9.1 None

181 -CH,-l:J None 0.1S

182 -CH,J:) 0.03 1.0

183 -(ClI ) -r-J 25 None" 0

184 -CH'D a 1.0

0

185CHD 0.8 None

-CH, 0

186 -CIID 0.3 0.05

CH1 0

a Relative to morphine = 1, mouse writhing test.b Relative to nalorphine = 1.

Analgesia

Antagonist

R Hot Platea Writhinga Activityb

CH, ;:) (R) Inactive 0.12 0.17H

CH'''!:) ~(5) 21 31 Inactive -'H 0

r<./,+ ~""t..\.-qg(>r>\':s.t ,I

CH,~~(R) Inactive 0.t8 O.ll

CH.,

CH;..Q (5) Inactive 9.2 0.53CH)

D (R) O.t7 0.36 Inactive(CH,)_' 0-H

(CH');'{~)(5) 0.34 1.1 Inactive

D (R) 0.03 {J.{)6 Inactive(CIt')'H 0

(CH,)""p(5) 0.15 O.tO Inactive

286 6 The BenlOmorphans

Table 6-21

Analgesic Activity of 3-HeterocycJic Alkyl Substituted

Benzomorphans

A variety of analogs containing a tetrahydrofuran ring in place of thefman ring have been prepared (Table 6-22) (/05). The compounds areagonists or mixed agonist-antagonists. The most interesting compound is188, MR-2034, which is much more potent than morphine. The impor-tance of tbe configuration of the newly introduced asymmetric center canbe indicated by comparison with its relatively inactive diastereomer (187).Increasing the length of the alkyl cbain or introducing a methyl group at

Table 6-22

HI Structure-Activity Relationships in the Benzomorphan Analgesics 287

Analgesic Activity of 3.Suhstituted Cyclic Ethers of Normctazocine

HO

Compound

187

188(MR-2034)

K-~.9.H'".~'''

189

190

191

192

193

194

a Relative to morphine = 1.b Relative 10 nalorphine = I.

110

AnalgesicCompound R Configuration PotencyQ

CH,I

195 CH,CHOCH, (5) 1241% (R) Inactive197 CH,-C(CH,hOCH, 3.1t98 (CH,hOCH, 157t99 (CH,hOC,H, 7.1200 (CH,hOC,H, 0.7201 (CH,),OCH, 1.6202 (CH,),OCH, 0.5


the new asymmetric center decreases the analgesic activity. The ll(:!isomer of 187 has 42 times the analgesic potency of 187, equivalent to 5times that of morphine. The 11(:!isomer in the (S)-series of 188 is one-halfas active as the lla isomer in the writhing assay (105).

MR-2034 (188) has been studied extensively (109); despite its stronganalgesic potency, it does not elicit typical morphine-like symptoms. Itdoes not cause physical dependence liability in monkeys. On the basis of itspharmacological profile and its affinity for the K receptor, 188 has beenlabeled a K agonist. A thorough investigation of its neurochemical prop-erties, however, indicates that MR-2034 binds extremely well to othersubclasses of the opiate receptor, including ",-I, ",-2, U',and 6 (110). It hasbeen called a universal opiate (100).

The realization that the compounds listed in Table 6-22 are cyclic ethershas led to the further simplification of the side chain and a dramaticincrease in potency. The ether 195, which possesses the two methylenegroups between the ether oxygen and the basic amino-nitrogen, as well asthe asymmetric center inherent in the tetrahydrofuran derivatives 187and 188, is 124 times as potent as morphine in the writhing assay and 4times as active as 188 (1/1). In contrast, the diastereomer of 195,196, isinactive. Further structure-activity investigations (Table 6-23) have re-

Table 6-23

3-Ether Substituted Normetazocine Derivatives

a Relative to morphine = 1, mouse writhing test.


vealed that the new asymmetric center is not important. The simple ether198 is even more potent as an analgesic than 195. The requirements forpotent agonist activity in this series are strict. Increasing or decreasing thealkyl chain on either side of the oxygen in 198 severely decreases potency,as does the addition of a second methyl group, 197 to 195 (/11,112). Theseopen chain ethers share the same K agonist features as the cyclic tetrahy-drofuran elhers.

C, The Inlroduction of Oxygen Containing Functions in the B- andC- Rings of Benzomorphans

1. Hydroxyl and Ketone Groups at C-I The C-I position in benzo-morphans corresponds to C-IO in the morphine alkaloids, and of the fewexamples known from the morphine series, this substitution effectivelyeliminates analgesic activity. In the benzomorphans, I-ketones are presentas part of the tetralone method of synthesis but are usually removed duringconversion to the targeted benzomorphan. The preparation of the epimericI-hydroxy compounds 204 and 205 was actually undertaken to study frozenconformations of noradrenergic ligands (113). However, the conversionsillustrated in Scheme 6-13 are general for the benzomorphans. Thebenzylic position (C-I) in benzomorphans is readily oxidized to the ketone(203), which can be reduced to the la-alcohol (204) or, through ahydroxyl inversion sequence, to the 1(:!-alcohol (205). The 6-methylanalogs of 203 and 204 have been prepared but, as would have beenexpecled, have minimal analgesic activity (/14). The la-substituted-l(:!-

206 (R. CIl3)

207 (R = C6115)

alcohols 206 and 207 are formed by grignard addition to l-ketometazocineO-melhyl ether. In the mouse writhing assay, tertiary alcohols 206 and 207have 2 and 10% of the activity of morphine, respectively (51). From thelimited number of examples available, it seems that oxidation at C-l in themetazocine series does nothing to improve analgesic potency.

An example of the preceding is shown in Table 6-24, where theJ-ketometazocine derivative (208) has only about 10% of the activity ofpentazocine (115). The other entries in Table 6-24 reflect the structure-

HO

Compound R'Analgesic Antagonist

R' R' Potency" Activityb

208 CH, CH, CH, 0.10 0.13209 (CH,),C,H, CH, CH, 0.52 Inactive2tO n-C3H, CH, CH, 0.70 3211 n-C)H7 C,H, CH, 2.2 t.45212 CH,CH~CH, CH, CH, 2.1 4.0213 CH,CH~CH, C,H, CH, 1.0 1.3214 CHrc-C)Hs CH, CH, 14 2.0

(ketocyclazocine)215 CH2-c-C3Hs ' CH, C2Hs 0.52216 CHz-c-C3HS C,H, CH, 49 Inactive

(ethylketocyclazocine)217 CHrc-C)Hs C2H5 fJ-CH, 1.0 2.0218 CHrc.C3H5 n-C3H7 CH, 1.5219 CHrc.C3H5 C,H, C,H, 15 18220 CHrc.C4H7 CH, CH, 0.56 Inactive

a Relative to pentazocine (150) = 1, mouse writhing test.b Relative to pentazocine = 1.

290 6 The Ber1Zomorphans

b-32 203 204

1

d,e,f

205

Scheme 6-13. Reagents: (a) Cr03, sulfuric acid; (b) sodium borohydride; (c) severalsteps; (d) CN8r; (e) 6% hydrochloric acid; (f) tosyl chloride, pyridine; (g) aqueous base; (h)lithium aluminum hydride.

activity relationships developed in the morphine, morphinan, and priorbenzomorphan analgesics. Of particular note is 214, ketocyclazocine,which is an agonist of similar potency to cyclazocine but possessingantagonist properties similar to those of pentazocine. Ethylketocyclazo-cine (216) is a potent agonist devoid of antagonistic properties. Interesting-ly, the IIj3 epimer (217) of ethylketocyclazocine (216) is merely as activeas pentazocine as an agonist and is twice as effective as an antagonist.Ketocyclazocine (214) and ethylketocyclazocine (216) possess a unique invivo pharmacology that distinguishes these drugs from classical /J.agonists.Inter alia, they do not substitute for morphine and do not precipitatewithdrawal in addicted rhesus monkeys. This led Martin to subdivide theopiate receptor and to designate ketocyclazocine as the prototype K ligand

III Structure-Activity Relationship~ in the Benzomorphan Analgesics 29t

Table 6-24

l_Ketobenzomorphans

(79). In general, K agonists lack both /J.and Ii receptor agonism. A general/J. antagonism is unlikely (116). Both 214 and 216 bind strongly to opiatereceptors in homogenized rat brains, with ICso values of 18 and 9 nm,respectively (97). However, besides having a high affinity for K receptors,214 and 216 have moderate to high affinity for /J. and Ii sites (117). Aneurochemical profile indicates that ethylketocycJazocine 216 is a /J.-2and Iiantagonist (118), which is a direct receptor antagonism and not a physiolo-gical one (116).

Reduction of the I-ketone with palladium and hydrogen in acetic acidyields the Ij3-aJcohol. The 3-cycJopropylmethyl derivative (221) has 0.2times the potency of pentazocine (150) as an agonist and 0.4 its potency asan antagonist. The 3-allyl derivative (222) is more potent, being 0.5 and 4times as active as pentazocine as an agonist and antagonist, respectively.Both 221 and 222 are more potent as agonists and antagonists than theI-ketone (208) (119).

HO

AnalgesicCompound R' R' R' Activity"

II CH, CH, H 0.7227 CH, H OH 0.02228 CH, OH H Inactive226 CH, CH, OH 0.t7225 CH, OH CH, 0.20229 C,H, CH, OH 0.t8230 C,H, OH CH, 0.7123t' CH, H OH 1.9232' CH, CH, OH 0.16

a Relative to morphine = 1, mouse hot plate assay.b 3-Phenethyl instead of 3-methyl.

292 6 The Be'hzomorphans

221 (R = CH2-C-C3HS)

222 (R = CH2CH=CH2)

2. A Hydroxyl Group at C-l1

A hydroxyl group at C-1I in the benzomorphans is equivalent to ahydroxyl group at C-14 in morphine, a substitution known to enhanceanalgesic potency and decrease side effects. The generation of a hydroxylgroup is acccomplished via the tetralone 223, which itself is readilyavailable from ,B-tetralone (ef. Scheme 6-1). Addition of methyl grignardto quaternary amine (223) yields predominantly the tertiary alcohol (226)in the a-methyl series, resulting from equatorial attack of grignard(Scheme 6-14). Addition to the free base (224), on the other hand, yieldsthe ,B-methyl series (225) resulting from axial attack (120,121). Catalytic

HO

224 22S

+ /CH 3N

'CH=0

3 a,c,b>

HO223 226

Scheme 6-14. Reagents: (a) methyl grignard; (b) O-demethylation; (c) pyrolysis.

l


Table 6-25

Analgesic Activity of I1-Hydroxybenzomorphans

reduction of the ketones gives similar results, forming the epimericsecondary alcohols. The ketone at C-ll is hindered, and grignard reagentslarger than methyl add either sluggishly or not at all (122). Biologically,the introduction of a hydroxyl group has been disappointing. Only thelIa-alcohol (230) is as active as metazocine (11) (120-122). A surprisingresult is that the secondary alcohol (231) in the phenazocine series is moreactive than the tertiary 6,1l-disubstituted compound (232) (Table 6-25)(120,121,123). The conclusion reached is that introduction of the equiva-lent of a morphine 14-hydroxyl group in the benzomorphans does not yieldthe potentiation of analgesic activity in the benzomorphan series. Anextension of the above study had included the results of a systematicexamination of the influence of epimeric ll-hydroxyl groups on benzomor-phans substituted at C-3 with traditional mixed agonist-antagonist andantagonist groups. The observation has been made that hydroxylationgenerally decreases analgesic activity. When the hydroxyl has the aorientation, it has a slight effect on antagonist activity. When the hydroxylgroup has the ,B orientation, it enhances the antagonist properties (124).

A series of 6-allyl and 6-n-propyl-ll,B-hydroxybenzomorphans hasbeen synthesized using the tetralone route (125). Both the allyl and

Compound R' R'Analgesic Antagonist

R' Activity" Potencyh233 CII, CII,CII=CII, II 6.03 <0.02234 CH2-c-C3Hs CII,CII=CII, II 0.63 2.0235 CHrc-C4H7 CII,CII=CII, H 0.17 0.54236 CHrc-C3Hs n-CJH7 H 0.71 1.6237 CHrc-C4H7 n-C3H7 H 0.20 0.40238 CII, CH,CII=CII, CII, 0.03 <0.02239 CHrc-C3Hs CH,CII=CII, CII, 0.001 8.2240 CHrc-C4H7 CH,ClI=CII, CII, 0.22 1.36

241 CII,-Q CII,CII~CH, CII, 0.001 0.75242 CII,-C=CII CII,CII=CII, CH) <0.001 0.70243 CHrc-C3Hs n-C)H7 CII, <0.001 13.2244 CHrc-C4H7 n-C)H7 CII, 0.28 0.84:Relat~ve to butorphanol == I, mouse writhing test.RelatIve to butorphanol==I, butorphanol==10 times that of morphine,1 times that ofnaloxone (ct. Table 5-18).

2946 Th: Benzomorphans

Table 6-26

Analgesic Activity of 6-AJlyl andProPyl-l1J3-hydroxybenzomorphans

n-propyl g~oups, together with the lla-methyl group, can conformational-ly approxImate the C-ring. in the morphinans. The biological resultspres.ented In Table 6-26 IndIcate that while opiate antagonist activity isretaIned when .co~pared to the morphinan butorphanol, the agonistproperties are slgmficantly decreased (126).

An lla-~ethoxyl group is present in moxazocine (245) (127). Theether (245) ISa mIxed agomst-antagonist that is equipotent to cyclazocine(151) as an analgesIc but has only about one-fourth its muscle relaxant and

~NS-depr~ssant properties (128). Moxazocine is effective clinically, caus-Ing a I.ow IncIdence of nausea. Psychotomimetic effects are observed at6-12 times the analgesic dose (129).

. 3. A Hydroxyl Group at C-6 A hydroxyl group can be readilyIntroduced at C-6 In benzomorphans by cyclization of the benzylpiperidone(246) wIth re/luxIng hydrobromic acid. During cyclization the methyl ether

j


N-CH2-<]

"lOCH)

245 (moxazocine)

HEr

HO

247

is cleaved to yield the 6;S-diol (247). A series of esters of 247 have beenprepared, but only the 6-acetate possesses significant analgesic activity(130).

D. A-Ring Substitutions and Replacements

The S-position in the benzomorphans corresponds to the 3-position inmorphine; for this reason, most of the A-ring substitutions have occurredat this position. The relative analgesic activities for a series of metazocinederivatives is shown in Table 6-27. It is readily apparent that theseanalgesic relationships approximate those in the morphine series, but anoxygen atom at C-S is not necessary for opiate activity (132). TheS-acylthio compound (250) is prepared by pyrolysis of the thiocarbamatederived from the S-hydroxy compound-the Newman-Kwart rearrange-ment (133). The synthesis of a series of derivatives of 250 bearing variousN-substituents has been reported (132). These compounds collectively arereported to be strong analgesics compared to morphine, with lessened sideeffects or physical dependence liability. The metazocine derivative 250 isapproximately as potent as metazocine but has only one-seventh of itsopiate receptor affinity (134). A series of benzomorphans containing /luoroand chloro substitution at C-S are readily prepared by Grewe cychzatlOn(135). All of these compounds are less potent and more toxic than eitherthe completely unsubstituted or S-hydroxy analogs (135). A nitro groupcan be readily introduced at C-S by nitration, and this can be reduced tothe amine (6). In order to demonstrate definitively that nitration occurred

CH3

256 (R1 CH3, R2 = H)

257 (R1 H, R2 CH3)

2966 The Senzomorphans

Table 6-27

Analgesic Activity of 8-SubstitutedBenzomorphans

R

Compound R Analgesic Potency a

911

248249250

HOH02CCH)OCH,SCOC,H,

0.08

0.7

l.Sb

0.21

0.61<

Q

Relative to morphine = 1, mouse hot plate assay.b

Reference 131.C Mouse writhing test.

at C-B, cyclazocine was subjected to the Birch reduction to give the enone(251). After oximation, treatment under Semmler-Wolff conditions re-forms the aromatic ring (252), which now contains an acetamide group atC-B (Scheme 6-15) (136). Hydrolysis of the amide to form the B-aminocompound yields an analgesic with properties between those of pentazo-cine and cyclazocine.

The replacement of the aromatic ring with a variety of heterocyclic ringshas been achieved, but in many cases only the synthesis has been reported.For example, the pyridoazocine (253) has been prepared by a lengthysynthesis, but no biological evaluation has been reported (137). Athiophene ring (254) can replace an aromatic ring in the benzomorphanswhen a thienylmethyl grignard reagent is used in place of benzyl in theGrewe synthesis (138). An extensive series incorporating the thiophenering has been prepared, but the compounds possess only weak analgesicactivity relative to their toxicity and no morphine antagonism (138). Apositional thiophene isomer (255) has been reported but not biologicallyevaluated (139). A thiazole ring analog of metazocine (256) and itsUI'!-isomer (257) bas been reported (140). The Uer-methyl (256) isapproximately equivalent to morphine as an analgesic, while the UI'!stereoisomer (257) has only 0.25 times the potency of morphine (140).Other more distantly related benzomorphans containing a thiazole ringhave also been reported (141).

III Structure-Activity Relationship!> in the Benzomorphan Analgesics 297

a,b

251

d

252

Scheme 6-15. Reagents: (a) sodium-ammonia; (b) hydrochloric add; (c) hydroxylamine;(d) acetic anhydride, acetic acid, hydrochloric acid.

253

N - CH)

254 255

E. BC-Ring Enlargements and Contractions

Various skeletal modifications of the benzomorphan alicyclic rings havebeen reported in studies attempting to determine the ring effects on phar-macological activity. These include both B- and C-nng contractIons to

2986 The Benzomorphans

a,b,c>

CH2C02CH3

IIo258

NH2"HCl

259

260 261Scheme 6.16. Reagents: (a) hydroxylamine; (b) H2/Pt; (c) hydrochloric acid; (d) base;

(e) B2H6; (f) Eschweiler-Clark reaction.

form norben20morphans and ring expansions to form B- and Coring

homoben20morphans, as well as both nor homo combinations. Many of

these syntheses have used methodology worked out in the parent ben20-

morphan series, and some of the derivatives have been found to be potent

analgesics.

1. B-Norbenzomorphans The synthesisof B-norben20morphans has

only been cursively investigated. The first synthesis started from an in-

danone aceticacid ester(258) (Scheme6-]6). Reductive amination fur-

nished the amino ester(259), which cycli2ed to the tricyclicderivative

(260). Hydride reduction of the lactam carbonyl group and subsequentN-methylation yielded the C-norben20morphan (26]) (142). The analgesicpotency of 26] is equivalent to that of codeine. The 8-desmethoxy

derivative of 261 retains one-third of the analgesic potency of 261 (143).

An alternativesynthesis of this nor-ring system (Scheme 6-] 7) employs thesubstituted piperidone 262, which undergoes a Lewis acid-catalyzedcychzalIon to the hydroxy norben20morphan (263) as a separable mixtureof methyl epimers. No biological activity has been reported for 263 (144).

2. C-Norbenzomorphans The C-norben20morphan (264) was pre-pared in a manner analogous to that of the B-nor compound (261)(145,146). The 8-methoxyl group was introduced by nitration and ulti-mately by decomposition of the dia20nium salt to yield the requisite


o a,b ).

262 263

Scheme 6-17. Reagents: (a) boron trifluoride, IlO.C; (b) LAH.

oxygenated derivative (265) (145). A simpler route starts from 7-methoxytetralone and yields the 8-hydroxy co.~pound (266) (147). Thephenol (266) has about 2% of the analgesic actIvIty of morphme (147). Afacileroute to C-norben20morphans has been descnbed;. however, Itrequires the presence of two aromatic methoxyl groups at posllIons 8 and 9(148).

R

264 (R = HI

265 (R = OCH3)

266 (R = OH)

267 268

3 B- and C-Homobenzomorphans The B-homoben20morphans havebee~ little investigated. The ketone (267) has been reported without ~nybiological data (149). Another B-homo variant has be~n prepared usmgthe Grewe reaction on a ]-phenylethyltetrahydropyndme mstead of the

usual I-benzyl derivative. The reported B-homo derivative (~68) possessesapproximately 25% oftheactivity of penta20cine (150). ThIS ISespecIally'nteresting, since the phenolic hydroxyl group IS m an unusual posllIon.

C-Homoben20morphans are readily produced uSI~g a chloropropyla-mine in place of the chloroethylamine in Barltrop s ongmal tetraloneapproach to ben20morphan (d. Scheme 6-1). The keto-C-hom~be~zo-morphan has served as a precursor to a variety of C-homodenvalIves(Scheme 6-]8). (151). The chemistry of this ketohomoben20morphanis interesting because it does not follow that of the analogous

=0

-CH3CH30

1

N-CH3

'CH3

CH30270

3006 The Btnzomorphans

-->

269

275

271 (R = CH3)273 (R = HI

272 (R = CH3)274 (R = HI

Scheme 6-18.

ketobenzomorphan (151). Addition of methyllithium results in a-additionto yield 269. In the benzomorphans, grignard or alkyllithium additionforms the llf3-alkyl-lla-hydroxy function. The alcohol (269) is extremelyresIstant. to dehydratl?n to the exo-methylene derivative (270) under awIde vanety of condItIons. The desired derivative (270), however, is alsoformed usmg a methylene Wittig reagent. Catalytic hydrogenation of270 gIves the f3-methyl (271) and a-methyl (272) compounds in 25 and 7%yield, respectively. The predominance of the f3-epimer is noteworthy, sincethe ll-methylene benzomorphan stereoselectively provides the a isomer.Hydrogenation of 270 under acidic conditions produces 271 in 85% yield.


Analgesic Activity of

C-Homobenzomorphans

Compound Analgesic ActivityQ

270273274275

0.131.20.411.1

Q Relative to morphine = 1, hotplate essay.

O-Demethylation yields the free phenols 273 and 274. Wolff-Kishnerdeoxygenation and O-demethylation furnish the monomethyl phenol (275).An alternative, more practical synthesis of the starting keto-C-homobenzo-morphan has been developed (152). The tertiary alcohol (169), equivalentto the 14f3-hydroxyl group in morphine, severely decreases the analgesicpotency of the molecule. The f3-methyl derivative (273) is more potent as ananalgesic than its a-epimer (274), parallel to observations in the parentbenzomorphans. The toxicity of the mono methyl C-homobenzomorphan(275) is so great that the analgesic activity reported in Table 6-28 is equivocal(151).

The unsubstituted parent (276) of the C-homobenzomorphan has beensynthesized without reported biological activity (153). A series of C-homobenzomorphans containing various substituents on the amine group

276

has been evaluated pharmacologically (Table 6-29) (154). The N-allyl andN-dimethylallyl derivatives (277-279) have either no or weak analgesicactivity and weak antagonist activity. On the other hand, the homo-cyclazocine analog (281) appears to be a pure antagonist with a duration ofaction equivalent to that of nalorphine.

The alternative C-homobenzomorphan has been synthesized using amodified a-tetralone approach where the Coring is formed in an intra-molecular Mannich reaction (Scheme 6-19) (155). The analgesic activities

-CH3

a b~-CH)O

CH) (CH2) 2NHCH)CH)O

CH)/CH)I

AnalgesicCompound R' R' R' PotencyQ

283 H H H 0.08284 OH H H 0.4128S OH H a-CH] 0.44286 OH H fJ-CH, 0.55282 OH CH] H 0.63287 'OH CH] a-CH3 0.85288 OH CH.~ fJ-CH, 1.1

a Relative to morphine = 1, mouse tail cuff assay.

3026 The S;nzomorphans

Table 6.29

C-Homobenzomorphans

CompoundC-II MethylConfiguration R

AnalgesicActivit yO

Antagonist

Potency b

277278279280281

TransTransCisTransCis

C!I,CH~CH,CH,CH~C(CH,),C!I,CH~C(CH,),

CHrc-C3HsCHrc-C]Hs

oo0.2o1.0

0.240.02

Very weakly active1.13.7

Q

Relative to pentazocine = I, mouse writhing test.b Relative to nalorphine = 1.

c-->

Scheme 6-19.HI.

282Reagents: (a) formaldehyde, hydrochloric acid; (b) LAH: (c) phosphorus,

III Structure-Activity Relationships in the Benzomorphan Analgesics 30J

Table 6-30

C. Homobenzomorphans

of the various ring-substituted derivatives are listed in Table 6-30. In thepresence of the phenolic hydroxyl, the effect of varying alkyl substitution isnot great, the most potent compound being 288, which is equivalent tomorphine. Compounds 282 and 287-288 have been resolved and possessthe expected properties (156). The levo-enantiomer of compound 282,eptazocine, has about one-half of the activity of morphine in a variety ofanalgesic tests, this activity being antagonized by naloxone. Eptazocinealso antagonizes morphine's analgesic effect (157). This C-homo-benzomorphan appears to be a mixed agonist-antagonist opiate (157).Marketing approval has been requested for eptazocine as an analgesic inJapan under the trade name Sedapain (158).

4. B-Nor-C-homo- and B-Homo-C-norbenzomorphans The B-nor-C-homobenzomorphans are of relatively recent vintage and have beenprepared in the expectation of producing a strong analgesic having neitherphysical dependence liability nor psychotomimetic effects (159). The initialsynthesis of this ring system employed a series of reactions previouslyunused in the benzomorphans (Scheme 6-20). A Diels-Alder reactionbetween benzyne, generated in situ, and cyclopentadiene forms the bicyclicsystem (289), which undergoes a [2 + 2J cycloaddition with isocyanate to


289 290

d-->

If)

e-->

291Scheme 6-20. Reagents: (a) cyclopentiaiene, magnesium; (b) chlorosulfonylisocyanate;

(e) Na,SO,; (d) hv; (e) LAH; (f) alkyl halide.

form the j3-lactam (290). Photochemical reverse [2 + 2] ring openinggenerates the functionalized B-nor-C-homobenzomorphan, which can bereduced to the parent B-nor-C-homobenzomorphan (291). A variety ofsubstituents have been introduced on nitrogen, but the most active is theN-methyl (291, R = CH3), which has 20% of the activity of morphinewithout substituting for or antagonizing it (159). An alternative large-scalesynthesis of the N-methyl-B-nor-C-homobenzomorphan (292) has beenreported (160). To introduce the requisite phenolic hydroxyl, a moreprosaic approach using a methoxylindanone has been used in an alternativeB-nor-C-homobenzomorphan (161). Surprisingly, the phenolic derivative(293) is inactive as an analgesic. Derivatives with a variety of other agonistand antagonist nitrogen substituents are very weak analgesics whencompared to morphine (161).

The B-homo-C-norbenzomorphans have been even less thoroughlyinvestigated. While successful synthetic approaches have been described,no biological data have been made available (162-/64).

F. More and Less Complex Benzomorphan Analogs

Models of the opiate receptor at the molecular level explain agonist andantagonist effects by the interaction between receptor sites and thefunctional sites of the analgesics (165,/66). The direction of the lone pairon nitrogen is considered to be important in determining agonist andantagonistic properties, but the models are diametrically opposed in termsof direction. One model requires the lone pair to be equatorial (165), whilethe other emphasizes its axial direction (166). A series of rigid analogs

III Structure-Activity Relationship!> in the Benzomorphan Analgesics 305

HO293 292

294.

295

HO

296 (n=l)297 (n=2)

(294-297) of pentazocine have been synthesized (/67). Thes~ derivativ~sall possess rigid stereostmctures: the. piperidine rings ~re In the chairconformation with the nitrogen lone paIr aXIal. The bIOlogIcal properties ofthese molecules are, however, quite different (168). The analgesIc poten-cies of the seven-membered analogs 295 and 297 are less than those ofpentazocine, while the six-membered ring analogs 294 and 296 are almostinactive. The latter pair have antagomst properties, whIle the formerpotentiate morphine analgesia. All have strong affimty for the opl~tereceptor. The conclusion reached is that lone pal.r dlfectlOn. IS not cmctalfor discrimination between agonist and antagomst properties.

Benzazocines and benzazepines, which result when the ll-carbon atomin benzomorphan is removed, have been investigated as analgesIcs (169).

AnalgesicCompound R' R' R' Potency"

298 CH, CH, CH, 1.4299 CH, CH, CH2-c-C3Hs 0.74300 CH, CH, CH,CH~C(CH,), 0.31301 C6HS H CHJ 0.06302 C6HS H CH2-c-C3Hs Inactive

a Relative to morphine = 1, mouse writhing t~st.

HO

AnalgesicCompound n R' R' R' Potency"

303 1 CH, CH, CH2-c-C)Hs 1.6304 1 CH, CH3 CH,CH~CH, 1.0305 1 CH, CH3 CH,CH=C(CH,), 1.7306 2 CH, CH, CH,CH=C(CH,), 0.25307 2 CH, CH, (CH,),C,H, 0.16308 2 CH, H CH) 1.0

2 CH, H CHz-c-C3HS -'309!>.,2 CH, H CH,CH~CfI, -'310

a Relative to morphine:o::1, mouse writhing assay.b Opiate antagonists.

3066 The Benzomorphans

Table 6-31

Benzazocine Analgesics

The ring system is prepared by cyclization of N-dimethylallyl or cinnamyldimethoxyphenylethylamine (170). Several of these flexible moleculesshow surprisingly potent analgesia (Table 6-31). Of the dimethyl deriva-tives, the N-methyl compound (298) is more potent than morphine;however, the mono derivatives have little, if any, analgesic activity (170).The requisite phenolic hydroxyl in the benzazocine and benzazepine ringsystems has been prepared. The benzazepines initially were synthesized bythe Bischler-Napieralski reaction (17l). The benzazepine analogs ofcyclazocine (303), SKF- 10047 (304), and pentazocine (305) are all morepotent analgesics than morphine (Table 6-32) (172). Antagonist propertieshave not been reported. On the other hand, the dimethyl substitutedanalogs in the benzazocine series (306-307) are relatively weak analgesics(173,174). Surprisingly, the monomethyl analog (308) is twice as potent asmorphine (175,176). However, in this case, the cyclazocine (309) andSKF-l0047 (310) analogs are potent opiate antagonists with no apparentanalgesic activities (169). Both 309 and 310 induce a phenomenom called

-------the quasi-morphine withdrawal syndrome (177). These drugs, )r09 and 310...]produce the effects of morphine withdrawal; however, this occurs innonaddicted, normal rhesus monkeys (177).

G. Nitrogen Movements within the Benzomorphan NucleusPlus Nor and Homo Derivatives

A great deal of effort and ingenuity has gone into the synthesis ofnitrogen positional isomers as well as the nor and homo analogs of


Table 6-32

Analgesic Activity of Benzazepine and Benzazocine Derivatives

benzomorphans. On the whole, the biological results of this extensiveinvestigation have been disappointing. One of the earhest IDvestIgatlOnslisted the syntheses of five different posItIOnal Isomers (311-315) (178).

311 312 313

314 315


Table 6-33

Analgesic Activity of the Nitrogen 4-PositionalIsomer of Benzomorphan

HO

Compound R Analgesic Potency"

316317318319

Ha-CHJfJ-CH,H'

1.10.330.28

<0.18

"Relative to codeine = 1, mouse tail clip test.

b 8-Desoxy compound.

The analgesic properties of derivatives of some of these positional isomerswere subsequently reported. Derivatives of 315 containing an 8-methoxygroup (benzomorphan numbering) and either 6-methyl (179) or 6,11-dimethyl substituents (180) have been prepared. Compounds of this typehave not been found to be useful analgesics.

The positional isomer (311) in which the amine has been moved toposition 4 has been more extensively investigated (181,182). As shown inTable 6-33, movement of the nitrogen from position 3 to position 4seriously diminishes the analgesic activity, particularly since the analgesicactivity is compared to that of codeine rather than morphine (183).Surprisingly, the dimethyl compounds 317 and 318 are almost equivalent inanalgesic potency to the 8-desoxy monomethyl compound (319). Antago-nist activity resulting from this substitution has also been disappointing(181). A further shift of the nitrogen to position 5, compound 312 with an8-hydroxy group, yields an analgesic with one-half of the potency ofcodeine (147).

A series of nor compounds in which the nitrogen has been moved toposition 4 (320) possess little antinociceptive activity in the hot plate assay.Those wIth N-antagonist substitution also have little, if any, antagonistproperties, but all are very toxic (184). The C-nor derivative 321 is aboutone-quarter as active as codeine in the tail clip assay (147). The C-homo

III Structure-Activity Relationships in the Benzomorphan Analgesics

320 (R = CH3, CH1CH=CHZ'

CHZ-C-C3HS' CH2CH=C(CH3)2)

324

326

309

HO

321

HO

325

derivatives 322 and 323 have, at most, 10% of the activity of morphine(147,185,186).

A variety of compounds more distantly related to the benzomorphanshave utilized both nitrogen and bridge head position shifts. For instance,the bridged benzocyclooctane 324 has been reported (187). Compound325 has about one-half the activity of penlazocine in the mouse writhingassay. The nor compounds with N-phenylethyl and dimethylallyl related to325 are substantially less active (188). Variation of the nitrogen substitu-tion in 326 does not yield a compound with more than 10% of the activityof cyclazocine as either an agonist or an antagonist (189).


HO HO

322 323

The addition of another nitrogen to the benzomorphan ring (aza-benzomorphans) has a deleterious effect on analgesia (190).

IV. The Chemical Anatomy of the Benzomorphans

The tricyclic structure shown in Fig. 6-2 represents the absolute con-figuration of analgesically active enantiomers of the synthetic molecules.All known active compounds are levorotatory. The dextrorotatoryenantiomers are either less active or inactive as analgesics. The benzomor-phans have the same absolute configuration as morphine at atoms 2 and 6.On the basis of the structure-activity relationships developed in SectionIII, analgesic activity in the benzomorphans shows the following trendswith functionalization:

I. An aromatic A-ring with a phenolic hydroxyl at C-S displaysanalgesic activity, although the hydroxyl group is not necessary foranalgesic effects. Methylation of the phenol reduces activity several-fold.

2. A lower alkyl substituent at C-6, preferably ethyl or propyl,enhances analgesic activity.

Ketone at Co,

CHz.CO

~ , 'Ifphenyl. thienyl. furyl

,.'

N'CH,Ln:", ,..-..

" '~orfCHzhO-alkyl

"~Mono or di.alkyl substitution. or fCH1hCOR at C-' 1,

:.lower alkyl groups at C.G

,,<

Hydroxy group at C-B

Fig. 6-2. Analgesia potency-enhancing substituents on benzomorphans.

,,

References 311

3. A lower alkyl group at C- II, usually j3-methyl or j3-ethyl, displaysanalgesic activity, the a-compounds being less active as a rule. Thepresence of a ketone y to the ring at C-l I can increase morphino-mimetic activity up to IOO-fold.

4. Alkyl groups at C-6 and disubstitution at C-l I can increase analgesicactivity several hundredfold.

5. The N-methyl-substituted benzomorphans, with or without alkylsubstituents at C-6 and C-lI, can possess opiate antagonist activi-ties. This activity resides in the levo isomer. In some cases, thedextro isomer can substitute for morphine.

6. Varying the nitrogen alkyl group length yields agonists at methyl,antagonists at propyl, and agonists again at pentyl. A methoxyethylgroup increases analgesia to 157 times that of morphine.

7. Replacing the N-methyl with phenyl ethyl or heterocyclic ethyl canincrease the analgesia by up to 25-fold over morphine.

S. The use of unsaturated or cycloalkylmethyl substituents on nitrogenyields either mixed agonist-antagonists or antagonists. The N-allyl(SKF-IO047) serves as the prototypic ligand for the "opiate receptorthat governs mania and other psychotomimetic effects. Thedimethylallyl substitution gives pentazocine, which is a clinicallyuseful mixed agonist-antagonist analgesic.

9. Introduction of a ketone at C- I with various N-substitutions formsmixed agonist-antagonists. Ketocyclazocine is the prototypic ligandfor the opiate K receptor. The K agonists do not cause the physicaldependence liability observed in the J1.agonists such as morphine.

10. Introduction of a hydroxyl group at C- II, analogous to the potency-enhancing C-14 group in morphine, is not consistent with stronganalgesia.

II. Ring contractions and enlargements usually decrease activity. Ex-ceptions are some C-homo derivatives.

12. Movement of the nitrogen is not advantageous.

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JI26 The Benzomorphans

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I

~

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7.Piperidine Analgesics

I. Introduction . . .H. Meperidine Family.

A. Synthesis . . . . . . . . . .B. Structure-Activity Relationship!>C. Clinical Utility ... . . . . . . . . . .D. Ring-Expanded and -Contracted Analogs

III. Bemidone Family .

A. Synthesis . .. ......B. Structure-Activity Relationships

IV. Prodine Family .A. Synthesis . . . . . . . . . .B. Structure-Activity Relationships

V. Alkyl Family . . . . . . .A. 4-Alkyl-4-Arylpiperidines .B. 3-Alkyl-3-Arylpiperidines . . . . . . . .C. Ring-Expanded and -Contracted Analogs. . .D. Conformationally Rigid and Bridged Analogs.

VI. Anilino Family . . . . . . . . . . . . . . . .A. Synthesis . . . . . .B. Structure-Activity Relati~nsh'ip~: G~n~r~ti~n 'of'C~~~u~d's ~ilh Cli'ni~ai

Utility . . .. . ...........C. Rigid Analogs and Conformational ExplorationReferences

318319319321328328331331332334335337352352354356359362362

363366367

I. Introduction

.One of the m~st intensely studied morphine-like synthetic analgesics,

mtroduced by Elsleb and Schaumann in 1939 (1), is ethyl I-methyl-4-phe~ylpiperidine-4-carboxylate, known by 20 synonyms (2) althoughofficially named meperldme and commonly called pethidine in the UnitedStates. Structure-activity relationships in the synthetic piperidine analge-SICShave been. explored at numerous positions of the molecule, leading toa most extensive data base that is still growing. Structural types can begrouped into five major classes: (a) 4-carbalkoxy, the meperidine family;(b) 4-ketoxy, the bel~ldone family; (c) 4-acyloxy, the prodine family; (d)4-alkyl; and (e) 4-an.lhno, the fentanyl family, the later class containing themost potent synthetic analogs. The substituted piperidines are distinguish-able from morphme by theIr structural simplicity and increased stereo-chemical flexibility, and have therefore spawned intense interest as recep-

JI8

II Meperidine Family JI9

R

~, heteroarornatic, oxygen functionality:-C02R, -OCOR, -COR, -01

e .g., /[J)...o

Ar

fC H

/n 2n

N11R

1.2.3n

H, Meespecially 3-Me

. Me, alkyl, phenylalkylaralkyl

Fig. 7-1. Structural modification of 4-arylpiperidine analgesics.

tor probes, allowing the development of hypotheses about the structuralrequirements of the analgesic receptor.

The first four family structural types have been extensively studied andreviewed (3-10a) for synthesis, pharmacology, and addiction liability.Major beneficial modifications of the general formula of the 4-arylpiperidines are shown in Fig. 7-1, where the C-4 substituent is thedeterminant of the classification, R3 being primarily an oxygen-containingfunction: carbalkoxy, acyloxy, alkyl ketone, alkyl ether (or related alkyl).R1 includes methyl and other related alkyl and phenylalkyl groups. R2 ishydrogen and methyl. The aromatic group is unsubstituted, or contains avariety of functional groups, or is replaced by heteroaromatic groups. Andn is 2, 1, or 3 for the classical six-membered piperidine ring and thecontracted 5- or expanded 7-azacycloalkyl ring analogs.

II. Meperidine Family

A. Synthesis

The first synthesis of meperidine (4) was reported by Eisleb (11), withlater modifications described by others (3,8,12). Through the years, the

320 7 Piperidine Analgesics

R

b

(or f)

R3

R

3 1 Z4 R = R = H, R = CH3, R = CzHs

1 3 Z5 R = R = R = H, R = CZHS

Scheme 7-1. Synthesis of 4-carbalkoxy-4-arylpiperidines. Reagents: (a) NaNH2.R 'N(CII,CH,X,h; (b) NaNH" YCH,CH, Y;(c) R 'NH,; (d) 11,50" R'OH;(e) bydrogenolysisor hydrolysis; (0 NaNH2. R 'N-CH2CH2 Y

ICH(R')CH,Y,

original synthetic schemes (Scheme 7-1) have remained the principalroutes to the meperidine family of compounds. The key starting material isthe phenylacetonitrile (I), which is converted to the 4-cyano-4-phenylpiperidine (2) either directly or via the dialkylated phenylacetonit-rile derivative (3), where Y is a substituent replaced by a halogen or

y

II Meperidine Family

~)N,

C H -Y-Arn 2n

x-c H -Y-AroE-

n 2n

~~ICH2CH2-Het

Scheme 7-2.

321

x-c H -Arn 2n }

~)NICH2CH2-Ar

Synthesis of normeperidine analogs.

arylsulfonyloxy group prior to ring closure. Acid hydrolysis followed byesterification yields the final alkyl carboxylate.

U R 1is a benzyl or benzenesulfonyl group, removal by hydrogenolysis orhydrolysis results in the l-H (nor) compound (5), which can then bereacted with the appropriate functional groups, according to the conven-tional methods for alkylating amines, to give several classes of derivatives(Scheme 7-2). The" and f3 forms of N-substituted 3-methyl meperidinesare prepared from the respective nor derivatives, obtained by separation ofthe racemic 4-cyano-4-phenylpiperidine intermediate.

B. Structure-Activity Relationships

Exploration of substituents and their positions in the meperidine,or pethidine, series has focused primarily on the C-4 position, in var-ious substitutions on the aromatic ring and in alteration of the oxygen

M Z

Meperidine N C

7 N S+

8 S (C) C


functionality, and at the N-l position, in numerous replacements for themethyl group. The effect of replacing the carboxy and amino groups withheteroatoms, of changing both the size of and the substituents on theheteroatom-containing ring, and of introducing conformational rigidityhave also been studied.

1. Meperidine Modifications In considering structural modification ofthe C-4 aryl and C-4 carboxylic acid ester, optimum functionality foranalgesic activity is found in meperidine, ethyl I-methyl-4-phenylpiperidine-4-carboxylate, itself. General findings are as follows(4,13,14):

1. Substitution within the 4-phenyl group generally reduces activity, forexample, o-OH, p-OH, p-NHz, the exception being particular orthoand meta substituents, for example, m-OH (bemidone family), whichenhance analgesic activity.

2. Moving the phenyl group and/or carbethoxy groups to an alternateposition reduces activity (15-17), for example, 3-phenyl (6, isopethi-dine), which is half as active as meperidine.

6

3. Changes to C-4 alkyl esters larger or smaller than ethyl reduceactivity, for example, isopropyl or methyl, although an adamantylester is advantageous for increasing both potency and duration ofaction (18). .

4. Substitution of the C-4 ester with ketones or ami des or hydrolysis tothe carboxylic acid reduce activity, the exception being a C-4 ketonewIth an m-OH phenyl substituent (ketobemidone family), although atetrahydropapaverine amide (BG-9) has been extensively evaluatedm the mouse hot plate assay, rat striatum, and guinea pig ileum; inthe last, It shows both agonist and antagonist properties (19).

Isosteric replacement of carbon by sulfur has led to a series of 4-alkylsulfone meperidine analogs (7) (20), a number of which (R

= ethyl,propyl, Isobutyl) are as effective as meperidine in mice (21,22). However,smgle Isosteric replacement of the ring nitrogen in meperidine by sulfur (8,R ~ ethyl) leads to a loss of analgesic activity (23). Addition of an ethylenebndge across the 2,6-positions (9), which then fixes the conformation of

II Meperidine Family J2J

""'OW'"

ICH3

R1

R

R

1R, R = C6HS' COZCZHS

9

1R, R = C6H5' COZCZHS

10

the 4-substituents (24), has been reported to give a (3(exo) ethyl ester thatis slightly more active (about 1.5 times) than meperidine in mice (25). The"ester (en do) is several times less active than the (3 and is more toxic inrats (26). The biological activity evoked has therefore been partiallyattributed to a conformation in which the aromatic and piperidine ringsapproach coplanarity (27), due to a flattened piperidine ring (26). Inaddition to the phenyl tropanes, the alkyl endo/exo-phenylazabicyclo[2.2.1]heptane carboxylates (10), which have similar potenciesin mice (28,29), have been used to investigate conformational properties ofthe 4-phenylpiperidine family. These series of rigid meperidine analogshave indicated that analgesic activity is not extremely sensitive to theconformation of the C-4-phenyl group. However, the biological responseis dependent on the position of the aryl substituent, as evidenced by thenarcotic antagonist, with a lack of analgesic properties, generated in a seriesof endo-carbomethoxy aryltropanes, wherein the aryl has been moved tothe C-3-equivalent position (30).

Meperidine (Demerol, Dolantin) is clinically useful in select situationsfor moderate pain management, such as in smooth muscle spasm, having apotency between that of morphine and codeine. Thus, meperidine is1/IOth to 2/lOths as potent as morphine. This rank order of relativepotency is generally consistent in various animal test protocols (31). Inmice and rats, meperidine is one-fifth to one-fourth as potent as morphine(32); in humans, 50-100 mg meperidine is equivalent to 10 mg morphine(33). Meperidine's toxicity is low, and its duration of action is shorter than

II Meperidine Family 325

Table 7.]

Analgesic Activities of 4-Carbethoxy.4-arylpiperidines

aC6HsR-N

C02C2HS

Analgesic Activity"

R Mice Rats Refercncesb

4< CII, 1.0 1.0 II5 11 0.3 0.5 43

11< C,II,(CII,h 2.5 2-3 44-4912 C,II,(CII,), 23 13-20d 48-5013 p-NO,C,II,(CII,h N.A/ 6 48J4< p-NII,C,II,(CII,h 3 II 20,48,50-52t5 C,II,NII(CII,h 64 101 58,5916' C,II,NII(CII,), 9 31 58,5917 C,II,CII~CIICII, (t) 32 29-40d 48,4918 p-NII,C,II,CII~CIICII, (t) N.A. 12 48,50,6119 CII,(CII,), . 7 7 32,41,62-64

20 f\2.5 3-7 65-67

O,--,N(CH2)2

21 C,1I,O(CII,h 10 3_Sd 68-7022 C,II,O( CII,). 18 10 68-7023 C,II,CII,O(CII,), 8 5-8 70-72

24 ~CH2O(CH2)2 77 t8-28d 70,71,73,74

25~(CH2)4

N.A. 24-33d 70,73,74

26< IIO(CII,hO(CII,h N.A. 5 75-7727< CoII,CO(CII,h 74_106d 275 49,78-8128< CoII,CII(OIl)(CII,h 99-150d 286 49,81,82

"References lOa,10b,I3. b Pharmacology and synthesis.t; Clinical utility. d From several laboratories. ~Not available.

3247 Piperidine Analgesics

that of morphine. Tolerance develops slowly, and addictive liability islower than for morphme (9). However, morphine-like side effects such asrespiratory depression, nausea, and vomiting are observable. Full clinicaland pharmacokinetic profiles of pethidine have been reported (34-37).

Cunously, mependme has a low affimty for opiate receptors, only 0.2%that of morphine (38,39), yet a hot plate analgesia about 10% that ofmorphine (32,40,41). Apparently, meperidine penetrates the brain mOrereadily and reaches 600-fold higher brain levels than morphine (42).However, the concentration of each drug necessary to achieve half-receptor occupancy (rat brain homogenate) corresponds to the brainconcentration at half-maximal analgesic response.

2. N-1 Substitutions Normeperidine itself (5) is much less active thanmeperidine (43). Studies of norpethidine analogs therefore have beenextensive, this N-] structural modification contributing the largest numberof analogs to the total data base. Most analogs are synthetically availablefrom norpethidine by alkylation with the appropriate alkylj aralkyl halideor by reaction with a suitably substituted aldehyde, aldehyde/ketone,epoxide, or olefin (Scheme 7-2). General findings are as follows (14)(Table 7-1):

I. Several phenylalkyl or heteroalkyl substituents increase the potencyover that of pethidine, for instance, phenylethyl (II, pheneridine),phenyl propyl (12), p-nitrophenylethyl (13), and p-aminophenylethyl(14, anileridine, Leritine). Anileridine is actually 3 times as potent aspethidine in the mouse hot plate assay, 10-12 times more potent inother animal assays (for example, rat radiant heat), and 2-3 timesmore potent in humans (34). ]n clinical use, equianalgesic doses ofanileridine and morphine are 25 and 10 mg, respectively (51,53-55).Whereas in the unsubstituted phenyl alkyl series peak activity occursat the 3-carbon chain length, in the p-amino and p-nitro phenylalkylseries peak activity occurs at the 2-carbon chain length. Chain branch-ing gives inactive or weakly active compounds. Compounds withother substituents on the phenylethyl aromatic ring display potenciesequivalent to that of meperidine or between those of meperidine andanileridine. N-acylanileridines have shown 4-40 times the activity ofmorphine in guinea pig ileum, but these activities do not correlatewith their analgesic potencies (56). Interestingly, however, a fumar-anilate derivative has shown a long-lasting antagonism to morphineanalgesia, which suggests a high affinity for analgesic receptors (57).The demonstrated antagonism of morphine analgesia is unique, sinceno antagonism has been found for the fumaranilate in dependentmice or guinea pig ileum. The compound's ability to alkylate

analgesic receptors selectively has been explored through its antago-nistic property,

2, Two isomeric anilinoalkyl derivatives (IS, 16) have higher activitiesthan anileridine (59), Piminodine (16, Alvodine), whose clinicalpotency is equivalent to that of morphine, has been marketed forpostoperative pain; 7,5 mg is equivalent to 10 mg morphine (60).


Substitution of an amide linkage [C6H,NHCO(CnH2)n] for NH doesnot improve activity.

3. Two unsaturated I-cinnamyl derivatives (17, 18) are extremely active.Alkyl groups up to nine carbons, the C-1O analog being inactive,confer slightly greater activity than meperidine, with n-hexyl (19)being optimum. This homologous series shows a good correlationbetween affinity, in the presence of sodium, for opiate receptorbinding sites and analgesic activity in the mouse hot plate assay (64).

4. An oxygen or sulfur functionality at a 2-4 carbon distance from thebasic nitrogen center results in good analgesic activity. A 2-morpholinoethyl (20, morpheridine) or 2-thiomorpholinoethyl sub-stituent, and several oxyalkyl derivatives, those with 2-ethoxyethyl(21), 2-ethoxybutyl (22), and 2-benzyloxyethyl (23, benzethidine)substituents, have potent activities relative to meperidine. Morpher-idine's analgesic activity in both rats and dogs is intermediatebetween those of morphine and pethidine (65); however, measure-ment of potency at 60 minutes shows morpheridine to be about 1.2times as potent as morphine (70). The thialkyl analogs are much lessactive than the corresponding oxygen ethers. The phenoxy deriva-tive is equipotent with benzethidine, but substituted phenoxy ana-logs are less potent than the unsubstituted parent. A quantum leap inactivity occnrs when substituting a 2-tetrahydrofurfuryl group (24,furethidine) and replacing the ether linkage (25). Both tetrahydrofur-furyl derivatives have approximately 25-35 times the potency ofmeperidine. These results have indicated that the maximum analgesicactivity can be found in an N-substituent of six or seven atoms or ofchain length 7-9 A. Simplified ethers, however, also have exploitablebiological properties, with the 2-(2-hydroxyethoxy)ethyl analog (26,etoxeridine) being commercially available in Belgium.

5. A series of aralkyl carbonyl- or hydroxyl-containing norpethidines,prepared from the reaction of norpethidine, formaldehyde, and anacetophenone 'or from condensation of an appropriate haloal-kyl aryl ketone and norpethidine, exhibit the highest activity of all4-phenyl-4-carbalkoxy derivatives. The 2-propiophenone derivative(27), with a 2-carbon alkyl chain, gives the maximum response at60-200 times that of pethidine in mice and rats. Lengthening orshortening the alkyl chain or placing substituents on the aromaticring generally decreases the potency. Ethyl is the optimum C-4 estergroup. The secondary alcohol (28, phenoperidine, Operidine)obtained from reduction of the 2-propiophenone is slightly moreactive than the ketone, with a similar activity profile, and has found


clinical application in neuroleptanalgesia, the administration of apotent analgesic with a tranquilizer (83). The R-( + )-enantiomer isfour times less active than the (- )-isomer but seven times morepotent than morphine in mice (82). The acetate is less active than theketone. Acetophenone and butyrophenone derivatives, ketones,alcohols, esters, and ethers, exhibit reduced activity compared to thepropiophenones. The amino analogs of the reduced acetophenonesare inactive (84).

Since the number of chemical modifications in the series of N-substitutednorpethidines is so large, a semiquantitative estimate of the influence ofthe above changes on analgesic potency in rats and mice has been made(49).

Interestingly, replacement of the N-methyl group with allyl (29) orcyclopropylmethyl (CPM) (30) does not generate an antagonist, as is the

29 R = CH2CH=CH2

30 R = CH2-<1

case in several morphine-based series (85-87). Only narcotic analgesia hasbeen observed in these series. In fact, N-allylnormeperidine is as potent asmeperidine, itself, having about 1/lOth the activity of morphine in rats(43). Methoxycarbonyl compounds with an N-I allyl substituent have alsoshown good analgesic activity, without any antagonism (88).

3. Ring Methylations One piperidine ring modification has beenstudied in some detail: addition of a 3-methyl group to meperidine andnormeperidine derivatives. Several 3/3-methyl meperidines with variousI-alkyl substituents have been synthesized (89), but their biologicalactivities have not been thoroughly explored. This cis (/3) 3-methyl-4-phenyl isomer of pethidine has been reported to be 8.5 times as active asthe trans (ex) in mice (90) and 12 times as active in guinea pig ileumlongitudinal muscle contraction (91). Alkyl 3/3-methyl carboxylatesof the parent I-cinnamylnormeperidine (17) and the parent 1-(2-ben-zoylethyl)normeperidine (27) have been studied (92,93).

328 7 Piperid1ne Analgesics

C. Clinical Utility

Compounds accepted for medical use include meperidine and nineN-substituted normeperidine relatives. Clinical potency parallels theiranimal potency (Table 7-1). The analgesic application and typical humandose administered, along with references for the date of introductionto the U.S. clinical market, have been summarized for each drug (5).

D. Ring-Expanded and -Contracted Analogs

Studies directed at the contracted 5-membered or expanded 7- and8-membered ring analogs of meperidine have been neither extensive norinteresting (13). The pyrrolidine analog of meperidine (31) as well as

C6HS

31

pyrrolidine derivatives are inactive (94,95). The 7- and 8-ring analogs areless active than the corresponding 6-membered piperidine analogs.

1. Synthesis Due to the lower activity of the azacyclopentanes, hep-tanes, and octanes compared to their piperidine counterparts, very fewanalogs have been synthesized. The principal syntheses (96-99) allowingvariation for the introduction of ring alkyl, usually methyl, and N-Isubstituents are analogous to the sequence for the piperidine series andinvolve similar key intermediates. For example, in the ring-expandedN-methyl derivatives, 4-dimethylamino-2-phenylbutyronitrile (32) is alky-lated with a 1,3-dihalopropane, followed by ring closure of 33 to yield a4-cyano-4-phenyl methyleneimine (34) (Scheme 7-3). The nitrile is thenhydrolyzed and esterified, giving ethoheptazine (35) and homologousesters. Using a dihalobutane in a similar process, the azacyclooctanes (36)are obtained (100).

Treatment of the starting nitrile (32) with trans-2-butenal (crotonaldehy-de) yields a dimethylaminohexanal that is converted via the alcohol andchloride to the 1,5-dimethylazacycloheptane nitrile (37) and ester (38)(Scheme 7-4). Using methacrylaldehyde or 3-buten-2-one (methyl vinylketone) in place of croton aldehyde generates the 6- and 7-methyl deriva-tives (39, 40) (99). The 2- and 3-methyl derivatives (41, 42) are synthesized


C6HS

XCN

(CH2)2 (CH2)nI I

N(CH3)2 X

33

a ,

32

35 n=3, R=C2HS

36 n =4

Scheme 7.3. Synthsesis of ring-expanded meperidine analogs. Reagents: (a) NaNH2,X(CH,)"X, (b) beal, -200"C; (e) acid hydrolysis; (d) H,SO" ROH.

by using /3-dimethylaminoisopropyl chloride and separating the resulting4-cyano-4-phenyl methyleneimines before completmg the Independentsyntheses (101,102). Using substituted phenylacetonttnles m the aboveschemes, derivatives with substituents on the aromatIc nng can be synthe-sized (97).

2. Structure-Activity Relationships The prototype of the hexa-methylene imine family, ethoheptazine (35, Zactane), IS less acllve than

C6a CH3d

(CH2)n <N-ICH3

37 n=2

le'f

C02R

CH3

(CH2)n

N../

ICH3

38 n=2

III Bemidone Family JJI

c'"r:/CH3

~CHCH3 3

39 40

CH3'::0'"

I

CH3

41 42

3307 Piperidioc Analgesics

b---+

a--7

32

Scheme 7-4. Synthesis of methylated azocycloalkane meperidine analogs. Reagents: (a)

NaNH" t-CH,CH=CHCHO; (b) NaBH,; (e) SOCI,; (d) heat; (e) H,SO,; (f)ROH.

meperidine in mice and about one-third as active in rats (IOa,103,104). Itdemonstrates no addiction liability (105) and is less toxic than codeine(98). Clinical interest (106-108) rests on oral efficacy against moderatepain in doses of 50-100 mg. It is commonly administered in combinationwith aspirin (Zactirin) (106,109). The 2- and 3-methyl derivatives ofethoheptazine are slightly more potent in the mouse (10a), with the3-methyl (42) appearing to be promising in animals due to an analgesicpotency greater than that of codeine or meperidine and few side effects(110). In humans, however, the methylated azacycloheptane analogsappear to be as active as ethoheptazine itself. Only ethoheptazine hasundergone extensive investigation, including clinical study.

.

Ill. Bemidone Family

Recognition of the structural similarity between the phenyljpiperidylrings of meperidine and the AID rings of morphine has led to explorationof the effects of a meta-hydroxyphenyl substituent equivalent, to C-3-0Hin morphine (111). The C-4 carboxy ester and ketone substituents with ameta-hydroxyphenyl constitute the bemidone and ketobemidone families.In rigid 4-phenyl axial morphinomimetics like morphine, a meta-OH isknown to enhance analgesic activity. In the bemidones, this substitutionhas complex biological and conformational implications (112-114) and hasproduced both strong agonists and antagonists, depending on the N-Isubstituent.

A, Synthesis

The synthesis of the alkyl meta-hydroxyphenyl carboxylates follows thatof Scheme 7-1, using the meta-methoxy substituted phenylacetonitrile andtreating the resultant methyl ethers with refluxing hydrobromic acid to givethe phenols. N-I substitution is accomplished by the usual methods fromthe norbemidones. From the 4-phenyl-4-cyano intermediate, reaction withthe magnesium grignard generates the C.4 ketones. In the ketobemidoneseries, the N-methyl and nor-compounds are obtained by the ethylchloro-formate method (115).

AnalgesicActivity

R R' R' in Mice" References b

Meperidine 1.047' CH, C2H~ OH 6 8,Il748 C,H,(CH,j, C,H, OH t49 c.H,NH(CH,), C3H7 H 9 Il8,Il950 C,H,NH(CH,), C,H, H 6 Il8,Il951 C,H,CH=CHCH, ~C,H, OH 0.9@ CH,(CH,), - N- f<' \ C,H, OH Qb 131,120)53 CH,(CH,), C,H, OH 1.6 31,12054 C,H,OCH,CH(OH)CH, C)H7 H 1.4 126

"References JOa,b,J3. b Pharmacology and synthesis. (' Clinical utility.

3327 Piperidin~ Analgesics


1. Substitutions Resulting in Antagonism General findings concerningantagonism in the bemidone family are as follows (116):

1. The free meta-hydroxy group on phenyl promotes antagonist activity.2. A C-4 ester or ketone, in conjunction, promotes antagonist activity,

wIth the methoxycarbonyl being the optimal functional group.3. N-substituents that are cyclic or acyclic but allyl-like promote antag-

Onism.

Bemidone (43) itself is 1.5 times as potent as meperidine in mice (4,5),so that introduction of a meta-OH into the meperidine structure actuallyincreases analgesic activity. The N-I allyl, dimethyl allyl, and CPMderivatives of bemidone fail to show much, if any, antagonism. Theimplication that the lack of antagonism in meperidine congeners is simplydue to the lack of a meta-hydroxyl group on the C-4 phenyl ring is provedincorrect by these structure-activity relationships. Other structural fea-tures seem important for nalorphine-like activity, for instance, shorteningof the ester chain.

In the carboxymethyl series, the N-I trans and cis 3-chloroallyl, dimethyl.ally, and cyclopropylmethyl analogs show various degrees of antagonismand agonism without displaying many morphine-type side effects. Thetrans 3-chloroallyl (44) is the most active antagonist of the bemidoneseries. Several cyclic allyl-like substituents (for example, 45) are antagon-ists in mice and/or monkeys. The simple allyl and several furfurylderivatives (46) have no antagonistic properties and show typical mor-phine-like side effects. Interestingly, N-I allyl and CPM derivatives ofketobemidone also behave like meperidine, having a morphine-like profileof action and failing to demonstrate any antagonist activity in morphine-dependent monkeys.

HO R

44

45

461

CH3' R = OCZHS147 R = CH3, R = CZHS

2. Substitutions in the Ketobemidone Structure Ketobemidone (47,Cymidon), a 4-m-hydroxyphenyl-4-propionyl

derivative of meperidine, is a

43

III Bemidone Family 333

Table 7-2

Analgesic Activities of 4-ketoxy-4-arylpiperidines

R2

strong agonist, being 10-12 times as active as meperidine and showing nonarcotic antagonism (8,34). Without the meta-hydroxyl, the compound isonly half as potent as meperidine. Ketobemidone is used primarily inEurope in a dose of 5-10 mg in humans, since its potency and duration areat least equivalent to those of morphine. Studies on norketobemidoneequivalents of normeperidines show (5) (Table 7-2):

1. The phenylpropyl substituent (48) decreases analgesic potency to themeperidine level but confers no antagonism or physical dependencecapacity.

2. Two anilinoalkyl derivatives (49, 50), as the 4-propionyl and 4-butyryl analogs, have greater activity than meperidine, but thissubstitution does not have the dramatic effect that is seen in meper-idine congeners.

3. The N-cinnamylnorketobemidone (51) is equivalent to meperidine inanalgesic potency. An ethyl group replacement for methyl almostabolishes activity, while larger alkyl groups show different effects ofagonism and antagonism. Only a n-penty substituent (52) is stron-ger than ketobemidone, by almost ree lImes; - exyl (53) and

R

0

6R3R3

aN ----?11R

57

58

1

b

R.~

J. OCOR2

" R3

3347 Piperidine AnalgesiC'S

N-heptyl chains are nalorphine-like (with 8% and 4% the potency ofnalorphine, respectively) antagonists with a long durations of action.In vivo potencies of the N-alkylnorketobemidones correlate well withmouse brain homogenate receptor affinities and antagonist activitiesin guinea pig ileum (/2l). Both agonist and antagonist potencies invarious animal models correlate well for this homologous series(/22). A 2-cyanoethyl group abolishes anti nociceptive activity (/23),unlike the positive effects seen in morphinans and benzomorphans.

4. An oxygen functionality at a fixed distance from the ring nitrogen, asin 2-hydroxy-3-phenoxypropyl, 2-morpholinoethyl, and tetrahydro_furfuryl compounds (/24,/25), does not dramatically increase activ-ity. The 2-hydroxy-3-phenoxypropyl derivative (54) is slightly moreactive than meperidine and is equipotent with codeine as a coughsuppressant.

5. Spiro analogs of ketobemidone, (55), obtained by reduction withsodium borohydride followed by treatment with hydrobromic/ aceticacids, as well as an isochromanspiropiperidine lacking any alkylappendages, are devoid of analgesic activity in mice (/27,/28). Theyhave very low affinities for opiate receptors in rat brain, but areinteresting to study as receptor probes, investigating with the rigidsystem the steric bulk and conformational requirements of thereceptor.

HO

55

IV. Prodine Family

The observation that reversal of the meperidine's ethoxycarbonyl groupto propionoxy (56), described by Jensen and co-workers in 1943 (/29),leads to a 5-10 times more active analgesic (4,/30), has led to exploitationof these esters of 4-aryl-4-piperidinols, called the reversed esters ofpethidine. This single modification generally accounts for a 20-fold in-

IV Prodine Family JJ5

crease in activity relative to meperidine, regardless of the nature of the N-1substituent (49). Investigation of analogs with 3-alkyl groups, ~Iong withall possible mono- and dialkylated analogs, has led to clarification of thestereochemical and conformational complexIty wlthm the senes and hasallowed correlation of molecular geometry with analgesic potency amongstereoisomers (/3l).

A. Synthesis

The synthetic route (/32-134) to the prodine family (Scheme 7-5), withor without a C-3 substituent, involves acylation, with an acid anhydride orchloride of a 4-aryl-4-piperidinol intermediate (58), obtained by additionof a lithi~m aryl derivative (preferred to an aryl grignard) or ~quivale~t toa 4-piperidone (57). Diastereomeric alcohols are produced If the plper-idone has an asymmetric center, for example, at C-3. These can beseparated into the Ct (R3-aryl trans) and /3 (R3-aryl cis) forms before

N11R

3 1 256 R = R = H, R = CH3, R = CZHS

Scheme 7-5. Synthesis of 4-acyloxy-4-arylpiperidines. Reagents: (a) LiAr; (b) (R2COhO,pyridine or R2eOCI.

3367 Piperimne Analgesics

A)R R

59

B)

b---c>

60

R

--e,f~

6157

58Scheme 7.6. Synthesis of piperidino! intermediates. Reagents: (a) CHlO, R INH2;

(b) R1NH2. CH2=CHC02C2Hs; (c) Na, xylene; (d) acid hydrolysis, heat; (e) NaH,R'X; (f) dilute HCI.

acylation if desired. When the lithium alkyl has bulky ortho substituents,for example, 2,6-dimethyl, only one isomer, the trans, is produced.

The piperidinol or piperidine itself can be obtained by several differentmethods. The piperidinol synthesis of Schmidle and Mansfield (Scheme7-6, scheme A), involving a 4-phenyl-4-methyl intermediate (59) synthe-sIzed from ~-methylstyrene, formaldehyde, and a primary amine, andg~vmg 30% YIeld, has produced unsubstituted piperidine rings (135). UsinghIgher a-substituted styrenes yields 3-alkyl piperidinols. For piperidineswith or without a C-3 methyl substituent, the 4-piperidone (57) can beobtained by Dieckmann cyclization of an iminodiester (60, R3

= H, CH3),

IV Prodine Family 337

followed by hydrolysis and decarboxylation of the 3-carbalkoxy-4_piperidone (Scheme 7-6, scheme B) (136-139). The iminodiester is synthe-sized from an amine and appropriately substituted acrylates, for example,ethyl methacrylate, followed by ethyl acrylate for the 3-methyl-4-piperidone product. Using methyl crotonate in place of the methacrylateyields the 2-methyl-4-piperidone (140). This synthetic route is not efficient,however, for C-3 alkyl substituents larger than methyl (141). An alterna-tive, more practical sequence for C-3 substituents involves alkylation of a3-carbalkoxy intermediate (61), followed by dilute acid hydrolysis. Mod-ification of the N-I substituent has been achieved either by choosing R' inthe amine, or by substitution reaction on the I-H piperidinol intermediates(58, R' = H), or by an exchange reaction between the methiodide salt ofthe N-methyl piperidone and a primary base R'NH2 (142).


The 4-acyloxy series of meperidine analogs has been primarily exploredby modification of the reversed ester group, substitution on/replacementof the aromatic ring, and substitution in the heteroatom-containing ring,each aspect being considered alone or in conjunction with exploration ofN-I substitution. Beyond this, the intermediate piperdinols and their alkylethers, along with ring-expanded, ring-contracted, and rigid analogs, havebeen studied.

1. C-4 Aryl and Ester Modifications Considering structural modifica-tion and/or replacement of the C-4 aryl and reversed ester groups, thegeneral findings are as follows (5,6,14,143,144);

1. Isosteric replacement of the phenyl with 2-furyl, 2-pyridyl, and2-thienyl (steric factor changes) decreases analgesic activity (145-149), although two 4-ethoxy derivatives (62, 63) have, respectively,3.6 and 1.6 times the potency of meperidine in mice and 1-3 times thepotency of morphine.

/"'1o

62 # - form

Analgesic Activity

R' R' R Mice".b Micet.".d

56 CH, C2Hs H 2.664 CH, CH, H 0.0965 CHJ n.C]H7 H 0.4466 C,H,(CH,1, C2Hs H 3.567 C,H,(CH,1, C2Hs o-CH] 3.468 C,H,(CH,1, C2Hs m-CH3 4.769 C,II,(CH,1, C2Hs p.CH, <0.370 C,H,(CH,1, C2Hs o,p-CH.1 0.566 C,H,(CH,1, C2Hs H 3.5

5.17

71 C,H,(CH,1, CH, H 6.3 5.772 C,H,(CH,1, CH, o-CH3 1.2 3.073 C,H,(CH,), CH, m-CH3 1.2 0.574 C,H,(CH,1, CH, p-CH, 0.5 N.A."75 C,H,(CH,1, CH, o-DCH3 N.A. 3.0

" References /34,143.b Morphine = 1. t."Reference 152.d Meperidine = 1. ..

Not available.

3387 Piperidine Analgesics

Table 7-3

4-Acyloxy-4-arylpiperidines

R

2. Replacement ~f phenyl with other unsaturated groups, groups thatare nonaromatIc but have a 7r electron cloud, for example, olefinic,acetylemc, or. ~aphthylenic, decreases the analgesic profile, althoughhot plate actIvIty may be retained (147,150,151).

3. Changmg the reversed ester from propionoxy to acetoxy or butyryloxy(56, 64, 65. m Table 7-3) generally reduces activity, the exceptionperhaps bemg the N-! phenethyl derivatives (66, 71 in Table 7-3)(49,134,152).

4. Substitution within the 4-phenyl ring (66-70, 71-75 in Table 7-3)generally red~ces activity, although ortho-methyl and methoxy sub-slItuents retam substantial activity; para substitution usually causesmore severe losses of activity than ortho substitution (134,152).


Table 7-4

Analgesic Activities of 4-Hydroxy- and 4-Ethoxy.4-arylpipcridines

QC6AS

RI_N

R2

R'AnalgesicActivity" ReferencesR'

76 C,H,(CH,1,77 C,II,CO(CH,1,78 C,H,(CH,1,79 C,H,N(COC,H,)(CH,1,80 C,H,N(COCH,)(CH,1,81 C,H,N(COC,H,)CH(CH,)CH,82 C,H,N(COC,H,)CII,CHCH,

O.6h40.35

50"6

150"20

152152/34156156157157

OC2HsOC2HsOHOH011OHOH

" References 134,152,156,157.b Mice, meperidine = 1. t." Rats, meperidine = 1.d Mice, morphine = 1.

Tertiary alcohol ('78 at 0.35 times the analgesic activity of morphine)and ether (76, 77 in Table 7-4) intermediates are usually devoid ofsignificant activity, even with potency-enhancing N-I or C-3-alkylsubstituents (134,153-155); exceptions are certain N-acylated linearand branched chain N-!-phenethylamine piperidinols (79-82 inTable 7-4), two N-(o-chlorophenylethyl) 4-piperidinols with a C-4N-disubstituted 2-propionamide group (4-propionoxy counterpartsessentially inactive) (158), and a rigid analog, a 3-azabicyclo-[3.3.!]nonane methyl ether (159).

2. N-l Substitutions Many N-! substitutions in the 4-acyloxy familyparallel those of the meperidine family and produce similar trends inanalgesic activity. General findings are as follows (Table 7-5):

I. Several phenylalkyl substituents increase activity relative to meper-idine, for example, phenylethyl (66), phenylpropyl (83), and phe-nylallyl (84). Peak activity occurs at a saturated chain length ofthree carbons (45,49). Two 2-oxazolidino-5-ethyl derivatives have in-creased activity, being equipotent with morphine in rats (161). A2-indanyl substituent, representing a conformationally locked phe-nylethyl equivalent, results in retention of activity equivalent tothat of meperidine (162) and of activity compared to loss 66.

2. The anilinoethyl derivative (85), analogous to the meperidine com-pound (15, Table 7-1), is extremely potent (1000 times the potency of


Tahle 7-5

Analgesic Activities of 4-Propionoxy-4-arylpiperidines

DC6H5R-N

OCOC2H5

Analgesic Activity"

R Mice Rats Refercncesb

Meperidine 1 1 1156 CH) 5-10 26 49,/29,/3066 C,Il,(CH,j, 17-25< 110 49,15283 C,II,(CH,h 162 572 4984 C,H,CH~CHCH3 (t) 261 1100 49,16085 C,H,NH(CH,j, N.A.d 1301 16386 C,H,N(COC,H,)(CH,j, N.A. 3 15687 F(CH,h N.A. 2200 /65,16688 C,H,CO(CH,j, N.A. 1346 16389 C,H,CHOH(CH,j, N.A. 3219 16390 C,H,C(OCOCH,)(CH,j,< 120 622 4991 C,H,C(OCOC,H,)(CH,j, 1000-1500 3040 49,/69,/70

a References JOa,b,13.b Pharmacology and synthesis. C From several laboratories.d Not available. ~ As 3-acetoxy.

meperidine in rats), although the acylated propionanilide derivative(86) has lost this remarkable potency. The anilinoalkyl compoundsalso lose activity when the nitrogen becomes tertiary, for example, bymethyl and ethyl substitution (164). The sulfur isostere of 85 losesalmost all activity (3 times that of meperidine), although the sulfoxideretains more (43 times that of meperidine) (163).

3. Several substituted alkyl derivatives, such as 7-fluoroheptyl (87) inthe 4-propionoxy series and 6-chlorohexyl-, 6-nitrohexyl-, 8-fluorooctyl-4-acetoxy piperidines, show enhanced activity relative tomeperidine, usually 250-1000 times that of morphine. The N-isopropyl-4-propionoxy analog is several times more potent thanmorphine in rats (147,167), although isosteric replacement withdimethylamino to give a hydrazine derivative abolishes all activity.This is particularly interesting, since the 2-morpholinoethyl analog isactive (168). In 4-acetoxy derivatives, the dimethylamino has onlyone-third the potency of the isopropyl isostere (134),which makes itinactive.

I

I

1

IV Pradine Family 341

4. As with meperidine analogs (28, Table 7-1), reduced derivatives ofaralkyl carbonyl substituents exhibit the highest activity of all4-phenyl-4-acyloxy compounds. While propiophenone (88) is about1300 times as active as meperidine, the N-(3-phenyl-3-propanol) (89)is 3200 times as active. The 3-propionoxy derivative (91) is almost aspotent as the alcohol, while the N-(3-phenyl-3-acetoxy) (90) shows adecrease in activity relative to the ketone.

3. C-3 Ring Substitutions Most of the investigations of the piperidinering have centered on substitution, especially with alkyl and aryl groups, atthe C-3 position and determination of the conformation and stereochem-istry within the resulting isomers (134,136,151,171,172). The relativeanalgesic activity of a- and ~-stereoisomers, along with differences in theantipodal forms of each, has been thoroughly studied (132). The racemic(d,l) forms of the diastereomeric a (trans) and ~ (cis) 3-methyl-4-propionoxy-4-phenylpiperidines differ in potency by a factor of 5 relativeto morphine in rats (173). Whereas a-methyl (92, alphaprodine), the mostabundant synthetic isomer, is equipotent with the 3-H unsubstitutedpiperidine (3-desmethylprodine), ~-methyl (93, betaprodine) has at leastthree times the potency of morphine.

C6XOC2H5

l )CH3

NICH3

93 II92 u

94

56

The influence of C-3 substituents as the a- and ~-isomers, however,does not always follow the trend of 3-methyl (174). However, the ~- (orcis) isomer is the more potent isomer of several 3-methyl 4-

AnalgesicIsomer C-3 C-4 Potency"

92 a-prodine (Oo) RS RS 7.0"(+) S S 13.3(-) S R 0.6

93 .8-prodine (Oo) RS RS 34.3"(+) S S 48.0(-) R R 4.6

S6 3-dcsmethj'lprodinc (-) 9.2,.

Reference J76.h Mice, meperidine = l.

" fJ/a -5.

342 7 PipcJ.:idine Analgesics

Table 7-6

Analgesic Activities of Prodine Isomers

q C6H5CH -N)

OCOC2HSCH)

Configuration

carbalkoxypiperidines. The 4-acetoxy and 4-butyryloxy {3-3-methylpro-dines decrease in activity relative to the 4-propionoxy equivalents byfactors of 4 and 3, respectively (24). !soprodines (94), isomers with thephenyl and reversed-ester groups moved from the normal C-4 position inthe prodine structure (56) to the C-3 position, are inactive (137,175).

Interestingly, the importance of the C-4 geometry is greater than that ofthe C-3, as demonstrated by studies of enantiomorphs of a- and {3-prodine(176). The two dextro (+ )-prodines, with different C-3 but identical C-4configurations, have greater potencies than those isomers with identicalC-3 and different C-4 configurations (Table 7.6). The most potent resolvedform of betaprodine is the (+ )-35,45, at eight times morphine, and that ofalphaprodine is the (+ )-3R,45, at three times morphine. Physical meth-odology has demonstrated a high skew-boat population in the more potentanalgesics, which means that the best biological response is attributed toconformations in which the aromatic and piperidine rings approachcoplanarity (24).

Alphaprodine (92, Nisentil) has been used clinically (now withdrawn) inselect situations. Its potency is greater than that of meperidine althoughless than that of morphine, in humans and animals, and its duration is veryshort (6,173,177). A 40- to 60-mg dose is equivalent to 100 mg meper.idine (5). Unfortunately, addiction liability is high (10a).


General findings for C-3 substitution, in conjunction with N-I substitu-tion, are as follows (Table 7-7):

I. Certain alkyl substituents produce a high increase in activity over3-desmethylprodine, for example, methyl, ethyl, and N-propyl. For3-methyl, the {3(cis) geometrical isomer (93) demonstrates the betteranalgesic activity (24,178), as seen in 3-methyl congeners of meper-idine, although for larger 3-alkyl groups, the a (trans) isomer is morepotent (174). The a-ethyl (95, a-meprodine) is eight times as activeas the {3(96, {3-meprodine) in mice, but biological activity can varydepending on the testing protocol, both isomers being equiactive incomparison to morphine (136). Interestingly, allyl represents thelimit in size for C-3 alkyl substitution, the 3-crotyl derivative fallingoff in activity. While the {3-allyl (98) is only 1110th as active asmorphine, the a-3.allyl compound (97, a-allylprodine) is 13 times asactive as morphine and 10 times as active as alphaprodine in mice(136,137). It has 60 times morphine's potency in rats but behaves as atypical narcotic analgesic (172). The analgesic al{3 isomer potencyratio for the 3-ethyl, 3-propyl, and 3-allyl propionate pairs has beenmeasured to be 8.8, 7.4, and 130, respectively (141,172). In theguinea pig ileum also, the a-allylprodine isomer has been found tohave superior agonist potency (91). Stereochemical studies of theallylprodines (171), therefore, have shown that the stereochemicalstructure-activity pattern for 3-alkyl reversed esters holds: the a(trans) isomer is more potent than the {3(cis), with the exception of3-methyl. This suggests a different mode of receptor interaction forthe a-alkyl isomers than for {3-prodine. The carbon-carbon unsatura-tion in the allyl group has been thought to enhance the enantiomericpotency of (d,l)-a-allylprodine. In comparison to the low activity of then-propyl analog, 97 shows a 24-fold increase in potency; comparisonto morphine shows a IS.fold increase. Receptor affinity studies of3-alkylated derivatives in rat brain homogenates have confirmeddiastereoisomeric al {3potency differences, with results correlatingwell with analgesic potencies (179). Higher receptor affinities arefound in a-alkylated esters rather than {3 (higher alkyls and allyl),with the reverse situation existing for methylated piperidines. Studieson the activities of antipodal forms of racemic a- and {3-3-alkyl-4-acyloxy-4-arylpiperidines have determined receptor discriminationbased on the enantiotopic edge of the molecule (6,180; see alsoChapter 8). In each case, the 45 configuration is more potent than the4R. An "Ogston" effect has been postulated to be operative in theligand-receptor interaction, the receptor having the ability to dis-

."0;;c<:~c'600:'0..~:~u<:

... u

"-

.,~~":c ;;. c

.... <:

~r! ~~........

~~~R:~~.........................

~~~~~~~.....................--

'"

IV Prodine Family HI

criminate configurational and conformational features in enantiomericligands (i.e., enantiotopic groups).

2. 3-Phenyl substitution in both a- and /3-prodine, and also on their4-acetoxy analogs, destroys activity. Benzyl is also disadvantageous(173).

3. N-I alkyl substitution shows a reduction in activity, the isobutyl-3-Hnorprodine analog showing intermediate activity between meperidineand alphaprodine. N-I allyl substitution does not produce narcoticantagonist activity. Quite the contrary; 99 shows over a fourfoldincrease in analgesia compared to meperidine, with no nalorphine-like properties but a high physical dependence capacity in monkeys.A 3,3-dimethylallyl substitution, unlike its potency-enhancing effectin the bemidone series, causes a 75% decrease in potency relative tomeperidine (181). Interestingly, a I,3-diallyl compound (100) seemsto be an extremely active analgesic in mice.

4. N-phenylethylnorprodines (101,102) show increased activity relativeto the prodines, with a relative potency similar to that of theprodines, the /3-isomer (101) being the more active, with 22 times thepotency of morphine (24,134).

5. Substitution on the phenyl ring in the prodine series usually decreasesactivity, as in the 3-desmethyl series (Table 7-3), one exception beingan artha-methyl in the 4-acetoxy analog (103), which is more activethan the 3-methyl-4-artha-tolyl-4-propionoxy equivalent or the 3-desmethyl-4-artha-tolyl-4-acetoxy derivative (72, Table 7-3). Thiscompound has been tested clinically for its effect on postoperativepain at a dose of 3-4 mg (5), since it is not only three to four times aspotent as morphine but shows separation of morphine-like activities(182). It is not clinically useful, however, since it produces severerespiratory depression. Replacement of phenyl by p-tolyl, o-tolyl,and m-tolyl gives progressively less active compounds (151).Hydroxyl substitution at the meta position in the prodines, theallylprodines, and the phenylethyl 3a-methyl compound (102) re-sults in compounds that are inactive as agonists and antagonists in ratsor mice (183,184). The phenolic derivative of 3-desmethylprodine isalso inactive, in contrast to 56, which has about 10 times the potencyof meperidine. The implication here is lack of a morphinomimeticreceptor interaction in these synthetic analgesics, since hydroxylsubstitution normally enhances analgesic activity in the rigid opiates.Activity differences between the phenolic arylpiperidines and mor-phine-type compounds have been attributed to divergent ligand-binding modes, whereby the phenolic piperidines mimic en kephalinrather than morphine binding (184).

C6HS C6HS

OCOCiis OCOC2HSJR,4S 3S,4R

3RAS Analgesic PotencyR Isomer Substitution Antipode AClivity".h Ratio

H (desmclhyl) 1.0CHJ a pro-4R (-)35.4R 0.06 45/4R-25

pro-4S (+)3R.4S 1.4CH:H~ a pro-4R (-)35.4R 0.04 4S/4W28

pro-4S (+)3R.45 0.94C.1H7 a pro-4R (-)3S.4R 0.03 4S/4R-25

pro-4S (+)3R.45 0.85CH,~CHCH, a pro-4R (- )3S.4R 0.11 45/ 4R -260

pro-4S (+ )3R.45 28.3

IIMice, subcutaneously. hot plate assay. b References /71,187-189.

3467 Piperidiqe Analgesics

Table 7-8

Analgesic Activities of Antipodes of a-Pradine Analogs

R

6. N-I anilinoalkyl substitution in the prodines does not have thedramatic effect seen in the unsubstituted reversed ester of meper-idine. N-methylanilinoethyl (104) increases activity relative to theprodines, but the potency of the N-ethylanilinoethyl drops by two-thirds, intermediate between that of 104 and meperidine.

7. As with meperidine analogs and 3-desmethylprodine, the propio-phenone derivative (105) is extremely active, almost 900 times asactive as meperidine.

8. N-I alkoxy groups, such as methoxy (106) and ethoxy, decrease theactivity of betaprodine to the level of meperidine, with other alkoxygroups being inactive.

4. Methylated Ring Analogs Resolution of the racemic a- and /3-prodine family of compounds has shed light on the relationship ofstereostructure to analgesic activity. Separation of a-3-methyl, 3-ethyl,3-propyl, and 3-allyl isomers has shown that the more potent activityresides in the (+ )-3R,4S antipode, where the 3-substituent is equatorial onthe pro-4S edge (Table 7-8).

Other mono- and dimethylated derivatives, [2-, 2,3-, 2,6-, 2,S- (prom-edols), 3,S- (isopromedols)], display complex activities depending on thestereochemical relationships in the antipodes comprising each racemic

1


CH) )_- 0 + HC=C-CH=CH2 --->

CH)

OHI

CH3-T-C=C-CH=CH2

CH)

c<--

promedolScheme 7-7. Synthesis of 2.S-dimethyl-4-piperidone. Reagents: (a) 50% H2S04;

(b)ltgSO,-H,o; (c) R'NH,.

diastereomer (6,14). Studies over the past 20 years have focused on theenantiotopic edges of the molecule (131):

. . .(1) the relative configuration of the substituents in the pipe~idinering, (2) the conformational equilibrium of each isomer, preferably In theprotonated state as solute in water, and (3) separatIo~ of chlral dt-astereoisomers into antipodal forms followed by estabhshment of theabsolute configuration and the analgesic potency of each member ofenantiomorphic pairs.

The syntheses of the 2,3-, 2,S-, and 3,S-dimethyl ring analogs have used,with various modifications, 4-piperidone syntheses that Involve reactIOn ofa substituted divinylketone and a primary amine, as shown for promodol(Scheme 7-7), and that result in a//3 mixtures. SynthesIs of the 2,6-dimethyl ketone follows either from Manmch reaction of dimethylacetonedicarboxylate and acetaldehyde or from catalytIc reductIOn andoxidation of the unsaturated 1,2,6-trimethyl-4(IH)pyridone and gives riseto different stereoisomer ratios. Synthetic methods for obtaining thesemethylated piperidines have been reviewed and summarized (131 andreferences cited therein).

Interest in the 2-methyl, 3-methyl, 2,3-dimethyl, 2,S-dimethyl, 2,6-dimethyl, and 3,S-dimethyI4-propionoxy arylpiperidines has led to specu-

=2"SR

R IsomerAnalgesic

Configuration Antipode Activity" References

3-CH, a 3e' d,1 7.7c 176,189pro-4R (-)3S,4R 0.6 176,189pro-4S (+)3R,4S 14.4 176,189

f3 3. d,1 40.9 176,189pro-4R (+ )3S,4S 52.4 176,189pro-4S (-)3R,4R 4.0 176,189

2-CH, a 2. d,1 O.65d.~ 140,191f3 2e d,1 0.65d....[ 131,175,191

pro-4R (- )2S,4R 0.75" 175pro-4S (+)2R,4S 0.07 175

2,3-CH, a 2a,3e d,1 0.53" 192f3 2e,3e d,1 0.03 192y 2a,3a d,/ 3.0 131,1928 2e,3a d,1 Inactive 6,192

2,6-CH)K Trans 2a,6e d,1 2.3Y 193Cis 2e,6e d,1 0.25 193Cis 2a,6a dJ Inactive 193

3,5-CH, y(107) 3ea,5ea d,1 2.29" 195pro-4S,pro-4R (+ )3S,5S 5.86 195pro-4S,pro-4R (-)3R,5R 1.15 195

Meso 3e, Se dJ Inactive 6Meso 3a,5a d,1 Inactive 6

a Mice, subcutaneously hot plate assay.t>a = axial, e = equatorial.CRelative to meperidine = 1. d Relative to 3-desmethyl = 1. "-3.5 relative to

meperidine = 1.f 0.75 relative to 3-desmethyl, ref. 99.g

As the 4-acetoxy derivatives.

CH3

Isomer Configuration Antipode Analgesic Activity" References

a' 2a.5ac d,1 26" 12' 188.191pro-4R, pro-4S (+ )2R,4S,5S 20 188.191pro-4S.pro-4R (- )2S,4R.5R Inactive 188.191

f3 2a.5e d.l 8.1 191,196y(108) 2e,5e d,1 2.9 1.3 191,197

pro-4S, pro-4R (+ )2S,4S.5R 1.3 19I.I97pro-4R, pro-4S (- )2R,4R,55 0.t3 19I.I97

S 2e, Sa d.l 2.6 131


Analgesic Activities of Ring Methylated Isomers of 4-Propionoxy-4-arylpiperidines

C6"S

lalion on Ihe pharmacological significance of conformation relalive to a~orphine-like or non-morphine-like binding mode (190). Biological activi-tIes of both racemic and. anlipodal forms of mono- and dimethylated4-proplOnoxy-4-arylplpendmes have been measured relative to eilher the3-desmethyl derivative or meperidine (3-desmethyljmeperidine, approx-Imately 10/1). The results from various laboratories are presented inTables 7-9 and 7-10 (prodines included for reference), with Ihe general

l

IV Peadine Family 349

Table 7-10

Analgesic Activities of Promedol Isomers

.D

a Mice. subcutaneously. hot plate assay.

"a/I3/8 potency ratio= 9/3/1 (8/2.5/1 as acetates).C a ::: axial; e = equatorial.d Relative to meperidine = l. ~ Relative to morphine = 1.

Irends describing the relalionship of slereoslructure to analgesic activitydiscussed in Chapter 8.

To resummarize Ihe potency of a- and (3-prodine, Ihe (+ )-anlipode withIhe 4S configuration is Ihe more polenl of each resolved pair, wilh(+ )-3S,4S (3-prodine being more than 50 limes as potent as meperidine.The potency ratio of racemic (d,/) l3/a-prodine has been consistentlymeasured as about 5.5/1, regardless of Ihe exact increases relative tomeperidine (191).

The racemic a- and (3-2-melhylpiperidines are equiactive, less activeIhan 3-desmethylprodine, but almost four limes as aclive as meperidine.The 4-aceloxy a or (3 race mates are much less aclive (140). The (3(Ievo)-2S,4R antipode, equipotenl with the racemate, is the more activeantipode by a faclor of 10 (175), which is twice as aClive as morphine.Opiale-binding sludies in guinea pig brain homogenales have shown aparallel potency difference, with ICso (3(- )/( +) values equal 10 9/1 (175).

In Ihe racemic 2,3-dimethyl-4-propionoxy piperidines, Ihe diaxial (y)isomer is Ihree times as active as the reversed ester of meperidine, which isinteresling, since this is 100 times the potency of the diequalorial ((3)isomer. The y slereoisomer has been reported 10 have 10-12 times Ihe


activity of morphine (6). A significant divergence is also found in theactivities of the a and S racemates. The a isomer has three-fourthsmorphine's activity; the S isomer is inactive. The {3-2,3-dimethyl isomerhas very low activity (practically none) due to unfavorable placement ofthe 2- or 3-methyl groups on either edge of the molecule (192).

2,6-Dimethylated analogs are mildly active. The cis-2,6-dimethyl-4-acetoxy analog, which has a disadvantageous pro-45 equatorial methyl, asin (dextro) {3-2-methyl, has one-fourth the activity of meperidine. The onlyactive racemate is the trans isomer, which is superior to the 3-desmethylparent.

The 2,S- and 3,S-dimethyl series of compounds (promedols and iso-promedols) are highly active, with some variation in potency among thediastereomers, which have been studied in conjunction with differences inactivity (131,190,194). Only one 3,S-dimethylated 4-propionoxy deriva-tive, the y-isopromedol (107, Isopromedol), is more active than meper-idine, by a factor of 2. The (+ )-35 ,S5 antipode is the more potent,equipotent with morphine, with the potency ratio of dextro to levoantipodes being S: 1.

Of the four 2,S-dimethyl isomers, the most potent is the S, with apotency equivalent to {3-prodine and a conformation with the two methylgroups cis to the 4-equatorial phenyl. The importance of this conformationhas been studied via rigid 2-azabicyclo[2.2.2]octane analogs, considered tobe locked-boat conformers of S-promedol, since the 2,S-dimethyl groupsare fixed in a cis-diaxial relationship (198). Racemic {3shows activity that isequivalent to that of the unsubstituted 3-desmethylprodine, approximately10 times that of meperidine. The a-2,S-dimethyl isomer (a-promedol) has12 times the potency of morphine, with the (+ )-2R ,45 ,S5 antipode being20 times as potent as both the 3-desmethyl and morphine (almost twice theactivity of the racemate). Curiously, the levo antipode is inactive. a-Promedol is 10 times more potent than y-promedol, whose activity residesmainly in the (+ )-25,45 ,SR configurational isomer. The potency ratios forthe a/{3/yracemates are 9/3/1, which remains constant in the 4-acetoxyderivatives as well (199). Interestingly, in the resolved promedols (a and

C H2 XOC2HS

CH3""l..)CH3

NI

CH3

107 (d,l) lOB (d,l)

IV Prodine Family 35\

y), the more potent antipode has the 45 configuration, as does resolved{3-prodine. The racemic mixture (108, trimeperidine, Promedol) hasdemonstrated increased activity relative to pethidine both in humans andin animals. Clinically useful at a 10- to 20-mg dose subcutaneously,superior to pethidine in both potency and duration of action (197), it isused in the U.S.S.R. for smooth muscle spasms, spastic conditions, andobstetrics (14,34). Isopromedol, the stereoisomer of Promedol, however,

CI has been reported to be a superior analgesic for smooth muscle pain.

5. Ring-Expanded and -Contracted Analogs The azacycloheptane(200,201) and azacyclooctane (100,202) analogs of the prodines have beensynthesized, usually via the usual Dieckmann cyclization route throughappropriate modification of the iminodiester intermediate. The pyrrolidinederivative and its analogs have also been made by Dieckmann cyclizationof an iminodicarboxylate diester to the 3-pyrrolidone, followed by additionof an aryl lithium and acylation (203). An alternate synthesis involves aN-carbethoxy-3-pyrrolidone intermediate, obtained by reaction of ana ,{3-unsaturated ester and a N -carbethoxy'a-amino acid, which is convertedto the 3-aryl-3-pyrrolidinol then reduced to the N-methyl analog andacylated (204,205). Modification of the sequences to yield the norpyrroli-dine analog of prodine allows introduction of N-l substituents.

Some ring-expanded analogs have been interesting pharmacologically,since they demonstrate clinically useful levels of analgesia with beneficialseparation of other opiate activities (9,206). The 3a-methyl azacyclohep-tane analog (109, proheptazine) shows 10 times the potency of meperidine,which is the equivalent of the increase observed for the prodines comparedto their 3-desmethyl counterparts (13). The 4-propionoxy, along with the4-acetoxy analog, however, produces high physical dependence inmonkeys (10a.b).

109

In the pyrrolidine series of prodines. results generally parallel those ofthe related meperidine and prodine families (reviewed in 5,6). Racemic2-methyl-3-propionoxy-3-arylpyrrolidine (110, prodilidine) is less potentthan either meperidine or codeine, but its physical dependence capacity is

AntagonistActivity ADso..,b

R C, Form Rats Mice

lit CH, {3 d,l 0.24 1.0112 CH, a d,l 33 39113 CH2CH~CH2 {3 d,l 0.47 0.72114 CPM< {3 d,l 0.72 0.72115 C6HsCH2CHz {3 d,l 0.11 0.t4116 C6HsCOCHzCHz {3 d,1 0.056 0.049117 C6HsCOCH2CHz {3 (+) 0.023 0.025118 C6HsCOCH2CHz (3 (-) 0.05 0.t4

Nalorphine 0.40 0.45Naloxone 0.022 0.079

" Milligrams per kilogram, subcutaneously.b Reference 211. C CPM = cyclopropylmethyl.


low (10a). The (+ )-enantiomer has 1.4 times the activity of the racemateby intraperitoneal injection, the (- )-isomer 0.6 times (207), although thisvaries on oral administration. Studies on modification of prodilidine haveshown that the 2-methyl is the optimal alkyl substitution, the 3-propionoxyis the best ester group, and N-I substitution does not dramatically improveactivity (208). In the last class, all compounds have activities less than thatof prodilidine, with the most beneficial N-I substitution giving a para-aminophenylethyl derivative potency merely equivalent to that of pro-dilidene. Norprodilidine also maintains the activity of the parent, but it ismuch more toxic.

Prodilidine (110) is the only compound that has been studied clinically(209), with several studies giving differing reports of its effectiveness.Nevertheless, 50- to lOO-mg doses have been used for ambulatory patientswith musculoskeletal disorders. Orally, it has analgesic properties similar tothose of codeine and greater than those of aspirin in potency, but it lacksaspirin's antipyretic and anti-inflammatory effects. It does not exhibitcardiovascular, respiratory depressive, antitussive, or constipating effectsat normal doses.

110

V. Alkyl Family

A. 4-Alkyl-4-Arylpiperidines

Exploitation of the biological effects in the C-4-alkyl substituted 4-arylpiperidines has provided a unique opportunity within the syntheticanalgesics to study a combination of agonist and antagonist effects.Narcotic antagonist behavior has been discovered in derivatives whereinthe C-4 position is substituted with alkyl and meta-hydroxyphenyl groupsand the ring nitrogen with a methyl group, not exclusively with allyl orcyclopropylmethyl, as found in rigid opiates. Various modifications of theparent, the potent 1,3,4-trialkyl-4-phenylpiperidine prototype, have in-cluded substitution on the aryl ring, methylation at and N-I substitution

V Alkyl Family 353

Table 7-11

Analgesic Antagonist Activities of 4-Alkyl-4-arylpiperidines

011

(210). Significant findings include the importance of a C-3-methyl groupand its isomeric and antipodal forms in contributing to antagonist prop-erties and potency differences (211).

The 1,3,4-trialkyl-4-phenylpiperidines (Table 7-11) are pure narcoticantagonists (211 ,212), as judged by their response in the mouse writhingassay, the electrically stimulated guinea pig ileum, and tritiated naloxonebinding in bovine brain homogenates, both in the presence and absence ofsodium chloride. The nitrogen substitution that increases agonist potencyin the meperidine family substantially increases antagonist potency. TheN-methyl compound (111) has antagonist activity close to that of nalor-phine both in rats and in mice; the allyl (113) and cyclopropylmethyl (114)do not have enhanced activity. However, phenylethyl (lIS) or propiophe-none (1l6) substitutions show a lOO-fold increase in naloxone competitive'binding and up to a 20-fold increase in potency compared to Ill, with 116being equivalent to naloxone. The f3 (trans 3,4-dimethyl) isomer is over 50times more active than the cis (a, 112). Resolution of the f3propiophenoneshows the (+ )-isomer (117) to be two to six times as potent as the(- )-isomer (lIS).

R R' Analgesic Activity EDso".'

122 CH, H 50.6t23 CH, a-CH3 Inactive124 CH, JJ-CH, -66t25 CH2~CHCH2 H -60126 C6H;<;COCH2 H 12.1

Meperidine 12.5Codeine 24.3

127 R : CHZCH2C6HS 130

128 R = CHZCOC6HS

129 R = CHZCH=CHZ


Comparisons of activities of 1,4-dialkyl, 1,2,4,S-tetraalkyl, and 1,3,4,6-tetraalkyl to those of the 1,3,4-trialkyl derivatives indicate that theantagonist activity is the result of a loss of intrinsic activity, not of receptoraffinity, which has implications for conformational requirements, studiedalso in cis and trans phenylpyrindines (119) and 2-methylphenylmorphans(120) (213,214).

HO

H

119 120 121

Changing a-methyl to a-C-4-n-propyl (C-4-n-propyljC-3-methyl cis)results in a mixed opioid agonist-antagonist (picenadol, 121), whoseoptical isomers show discrete separation of narcotic agonist and antagonistactivities. The racemate is twice as active as meperidine and one-fourth aspotent as morphine (subcutaneously or orally). The (+ )-isomer has a fullopiate profile and is l/lOth as potent as morphine but, unlike other fullagonists, has equal affinity for both IL and I) receptors, whereas the(- )-isomer is a partial opiate agonist (213). Picenadol has a desirableclinical profile, with its good therapeutic index and low physical depend-ence liability, and is used clinically in obstetrics (215,216).

B. 3-Alkyl-3-Arylpiperidines

Moving the C-4 substituents to the C-3 position (217) has allowed studieson 3-alkyl-3-(3-hydroxyphenyl)piperidines. both as ring-unsubstituted ana-logs and as C-2 or C-4 alkylated derivatives. These, plus 3-methoxyphenylsubstituted equivalents, have shown divergent activities, depending onthe N-l substituent and the C-3 alkyl group. The conventional synthesisinvolves hydrogenation of a cyano ester or ketone intermediate to give thecyclized 3-arylpiperidine, although other synthetic routes to 3-arylpiperidines have been reported and reviewed (218,219).

In C-3-methyl compounds, N-l substitution with large alkyl chainsresults in more potent analgesic activity, whereas in C-3-propyl deriva-tives, N-l preference is a small alkyl group (220). A 1,3-Dimethyl parent(122, Table 7-12) has only one-half the analgesic activity of codeine and

V Alkyl Family 355

Table 7-12

Analgesic Activities of 3-Alkyl-arylpiperidines

,.Milligrams per kilogram, mice, subcutaneously.

/> Reference 220.

one-third that of meperidine, but has lower toxicity in mice. Methylation atC-4, either a or {3 (123,124), as well as eliminating the hydroxy group,decreases the analgesic response; N-allyl substitution (125) does notimprove the potency. The N-l acetophenone derivative (126), however,has activity equal to that of meperidine and has a shorter duration ofaction than either morphine or codeine. Interestingly, its analgesic re-sponse is antagonized by nalorphine.

In 2,3-dialkyl-3-arylpiperidines, N-phenylethyl (127) and N-acetophenone (128) derivatives are approximately half as potent as mo~-phine in mice, with low toxicity (221). The 2-desmethyl analog of 128 tS

HO

III

!

~i

1

~1

il ,

i -f,,'j ~;j'

';1

"

Jt!,

R' R R' Analgesic Potencyll'.b

110 CH, CH, OCOC,H, 0.2131 H CH, (CH,hCH, 2.5132 H CH, CH(CH,h 3.0133 H CH, CH,CH(CH,h 2.7134 H CH, CH,C(CH,h 3.8135 H p-NH,C,H,(CH,h (CH,hCH, 5.8136 H CH, CO,C,H, 0.4

137 H CH, CH,CH~CH, 1.2138 CH, CH, (CH,hCH, 1.3139 CH, CH, CH,CH~CH, 0.9

140 H (CH,hCH, (CH,hCH, Inactive141 H (CH,),CH, (CH,hCH, 1.5142 H (CH,),CH, CH,CH(CH,h 2.5

" Rats, intraperitoneally.b Relative to codeine = 1.

" References 227,228.


equipotent with meperidine in mice. Both a (2,3-dimethyl trans) and {3(2,3-dimethyl cis) phenylethyl compounds are active, 0.7 and 0.33 timesas active as meperidine, respectively (6). Significantly, however, in thisseries, the N-allyl derivative (129) shows analgesia antagonized by nalor-phine and compound 128, but is devoid of analgesic activity. The {3isomersof N-allyl and N-CPM 2,3-dimethyl-3-(3-methoxyphenyl)piperidines aremore potent, with two to four times the potency of nalorphine (6). A reporthas confirmed the relative stereochemical assignments of the more potenta antipode, a(- )-I-allyl-2,3-dimethyl-3-(3-hydroxyphenyl)piperidine (222).Substitution of 3-methyl with 3-n-propyl or 3-benzyl in compounds 128 and129 eliminates activity. Receptor affinity studies indicate that the activecompounds in this series are pure agonists, the conformational adaptabilityof the 3-arylpiperidines being related to the rigid opiates (194,223).

C. Ring-Expanded and -Contracted Analogs

Ring-expanded and -contracted versions of the 3-alkyl-3-arylpiperidineshave yielded useful clinical prospects. The 3-ethyl-3-(3-hydroxyphenyl)azacycloheptane analog (130, Meptazinol), whose synthesis, isomer resolu-tion, and clinical profile have been amply reviewed (224), has exploitableagonist-antagonist activities (225,226). The two optical isomers show apotency equivalent to that of the racemate, which is equipotent withpentazocine in rats and has a similar antagonist profile. Meptazinol has alow incidence of side effects, however, and has been used for postabdomin-al surgery and for patients with acute renal cholic. 11also has the benefits ofrapid oral absorption and conjugation followed by excretion.

Contraction of the azacylo ring to pyrrolidine (227) with 3-propyl-3-(3-hydroxyphenyl) substitution produces an analgesic (131, profadol) 2.5 to 4times as potent as codeine or meperidine in rats, which is a considerableenhancement over prodilidine (110), the 3-phenyl-3-propionoxy pyrroli-dine. The side effects observed in various animal species, however, havebeen similar to those of prodilidine. The levo-isomer is twice as potent andtoxic as the dextro-isomer, but it is the racemate that has been evaluated inhumans.

Profadol is the prototype of the 3-phenylpyrrolidine series in which analkyl group replaces the previously exploited reversed esters related to theprodine family. Structural modification of the clinically useful analgesichave focused on the C-3 alkyl, hydroxyaryl, and nitrogen requirements foroptimal antinociceptive activity, with the same modifications that produceantagonists in the {3-prodines producing antagonists in the 3-arylpyrrolidines. General findings (relative to codeine) are as follows(228,229) (Table 7-13): 1

I

f(

I

V Alkyl Family 357

Table'.13

Analgesic Activities of 3-Arylpyrrolidines

I. Propyl and 3-hydroxyphenyl groups at C-3, as in profadol (131) itself,give the optimum typical antinociceptive response; limited chainbranching, for example, isopropyl (132), isobutyl (133), 2,2-dimethylpropyl (134), retains about the same level of potency; com-bination with N-methyl or beneficial N-l substitution, for example,para-aminophenylethyl (135), gives slight enhancement of analgesiaaccompanied by decreased lethality [note: methoxyphenyl with C-3-propyl (138) loses activity relative to 132].

2. Oxygenated (136) or unsaturated (137,139) functions at C-3 usuallydecrease activity in 3-hydroxy and 3-methoxyphenyls.

3. Substituted N-l phenylethyl substituents substantially increaseanalgesic potency; N-propyl substitution (140) results in a loss ofactivity; an increase in linear chain length to C-5 (141,142) againresults in analgesia, but with a potency less than or equivalent to thatof the N-methyl, a trend analogous to that observed in normorphineN-substitutions.

143 R CHZ-C-C3HS'R1 = CHZCH(CH3)Z

CHZCH = CHZ'1144 R R = CHZCH(CH3)

Z

145 R CHZCH = C(CH3)z'

1R = CHZCH(CH3)Z


Two modifications studied in detail have been N-cycloalkyl and N-unsaturated alkyl substitutions (230,231), since morphine agonists areconverted to partial antagonists by these changes. N-cyclopropylmethylproduces the best combination of analgesic and antagonist activities, withmanipulation of the length and branching of the 3-alkyl group modulatingthe potencies (maximum analgesia at n-propyl, isopropyl). The mostpotent racemate, 3-isobutyl-N-cyclopropylmethyl (143), has three timespentazocine's potency as an antagonist and exhibits potent antinociceptiveactivity against abdominal constriction in mice. The optical enantiomersare active in both morphine agonist and antagonist assays, in contrast to

HO

profadol, in which the (- )-isomer has greater agonist and the (+ )-isomergreater antagonist activity. Structure-activity relationships in the N-allylpyrrolidines compared to similarly substituted N-cyclopropylmethyl

,analogs show a lower antimorphine/antinociceptive ratio for allyl com-pounds. While 143 and the 3-isobutyl-N-allyl (144) have about 20 times thepotency of pentazocine in a morphine agonism paradigm (abdominalconstriction), 144 has over 10 times pentazocine's potency as an antagonist.Substitution in the allyl group reduces the morphine antagonism activity;for example, 3-isobutyl-N-dimethylallyl (145) suffers more than a lO-foldloss of analgesic response and a total loss of antagonism compared to thesimple allyl.

Interestingly, substitution of the 3-methylene group with N-methyl inseveral 3-alkyl-3-aryl (meta-hydroxy or meta-methoxy) pyrrolidines to givea set of pyrazolidines results in inactivity, the best of the series, a 4-n-propylderivative (146), having only half the potency of codeine (232). Ringcontraction to an azetidine analog of profadol (147) produces an analgesicpotency over twice that of codeine (233).

1

V Alkyl Family 359

HO

147

D 146

D. Conformationally Rigid and Bridged Analogs

Several series of compounds related to the alkyl arylpiperidines havebeen synthesized for use as narcotic receptor structural probes. Fromthese, both agonists and antagonists have emerged, with some modifica-tions producing mixed agonist-antagonist opiates. Each new analgesicseries has its own synthetic scheme and unique set of structure-activityrelationships, with several trends paralleling those of the meperidine andprodine families themselves. Although several attempts are being made torelate pharmacological findings to molecular conformations and bindingmodes, no conclusions have been universally accepted. The goal of thefuture is, therefore, to characterize narcotic receptor binding modes andexplain the structure-activity relationships of the synthetic arylpiperi-dine analgesics with information gained with these conformationally fixedprobes.

A summary of the structural types used for optimizing biological activityand for receptor probing is as follows:

1. J-Aryl-3-azabicyclo[3.1.0jhexanes, structure (A), cyclopropyl pyrro-lidines (rigid analogs of profadol): Examination of substitution withinthe aryl ring and of N-substitution has shown that the most potentmember of this series has para-methylphenyl and N-H substituents(234,235). Bicifadine (148), as a racemic mixture, with an analgesic

(A) (B)

NIR

148 149 R150 R =

x = 3' -OCH3X = 3' -OH

R H, X

(E) (F)

-R N-R

R1

X HO


profile in several animal models, has undergone clinical trials forpostoperative pain, but with unsatisfactory results (236). Physicalmethodology and X-ray crystallography have determined that the(+ )-enantiomer, in which all activity resides, has the lR,5S absoluteconfiguration.

2. I-Aryl-3-azabicyclo[3.2.0jheptanes, structure (B), homologs to (A):Examination of ketal intermediates has uncovered two dimethylketals (149,150), which have morphine-like analgesic profiles in miceand rats. The phenol (150) has tritiated naloxone-binding displace-ment ability equivalent to that of morphine (237). A molecularmechanics analysis of the 3-methoxy derivative has attempted torationalize this opiate-receptor binding (237).

3. Spiro[tetralin-I,3'-pyrrolidinesj, structure (C), conformationally res-tricted rotamers of profadol: Examination of substitution on the arylring and N-substitution gave inactive analgesics, even with hydroxy-lated phenyls (238). Two unsubstituted phenyl analogs (151,152)display activity equivalent to codeine.

(D)

x

151 R - Rl _ R2 = R3 _H 120 R - CH3, Rl = R2 - H,

152 R = CH3, R1

- R2 = R3 - H X _3' -DH

4. 5-(3-Hydroxyphenyl)-2-methylmorphans, structure (0), bridged 4-alkyl-4-arylpiperidine analogs: Examination of the racemate and theenantiomers of the parent (120) has disclosed different opioidprofiles: the racemate equipotent with morphine; the (+ )-isomerthree times more potent than morphine, with high physical depend-ence; the (- )-isomer equipotent with morphine but with weakmorphine antagonist properties in morphine-dependent monkeys(239). Substitution on the nitrogen, on the phenyl oxygen, and on thepiperidine ring (240-242) has indicated that while agonist potencycan be increased two to three times in the (+ )-isomers, antagonisticpotency in the (- )-isomers is not affected, even with cyclopropyl-methyl or allyl groups.

5. 5-Aryl-2-azabicyclo[3.2.ljoctanes, structure (E), conformationallyrigid analogs of hydroxyphenylmethylmorphan (0): Examination ofphenyl-hydroxy, -alkoxy, -acetoxy, and N-alkyl. -cycloalkyl, -aralkylgroups has indicated that an arylethyl side chain and 3-

l

V Alkyl Family 361

hydroxyphenyl or 4-hydroxphenyl produce the best analgesic activity(243,244). 3'-Hydroxy N-phenylethyl derivative (153) has an opiateagonist-antagonist profile (equipotent with morphine, half as potentas nalorphine), while 4'-hydroxy (154) is twice as potent as morphineand has weak binding affinity to labeled opiate receptors.

155 R R1 - CH31156 R CH3, R - H

6. I-Aryl-azabicyclo[3.2.ljoctanes, structure (F), both a bridged pro-fadol and a five-membered analog of the hydroxyphenylmethylmor-phans: Examination of N-substitution, ring substitution, and substitu-tion on the aryl ring has given mixed agonist-antagonists, derivativesdisplaying analgesic activities in the range of codeine to morphine yetalso displaying nalorphine-like antagonism (245). In the interestingenantiomeric pairs of 155 and 156, activity resides in the (+ )-isomer.The absolute configuration of (+ )-155 has been determined aslR,5S,7R, which is analogous to the absolute configuration of themore potent hydroxyphenylmorphan (+ )-enantiomer (246,247).This stereoselectivity again, as in the prodine series, suggests that theopiate receptor discriminates enantiotopic edges of the ligand.

7. Oxide-bridged (3-hydroxyphenyl)methylmorphans, (157,158), con-formationally restricted phenyl rings: In contrast to the (hydroxy-phenyl)methylmorphans with a freely rotating phenyl ring, theserestricted analogs have attempted to correlate torsional angles be-tween the phenyl and piperidine rings, as determined by X-rayanalysis, with opiate-binding activity (248,249,296). Testing hasshown that 157,158 are devoid of agonist and antagonist activity,although 158 has appreciable opiate receptor binding affinity.

153 R

154 R(CHZ)ZC6HS' X

(CHZ)ZC6HS' X

3'-OH

4'-OH

157 158


VI. Anilino Family

The 4-anilinopiperidine family has yielded the most potent anddistinct class of synthetic analgesics (6,144), related to both the arylpiperi-dines and open chain anilides (Chapter 9), as evidenced by their structure-activity relationships. The data base of compounds produced since theearly 1960s is enormous, a substantial subset of which is clinically effective.The general formula showing structural modifications in this family is givenin Fig. 7-2, where each positional modification has been evaluated alone orin combination with others.

A. Synthesis

Literature procedures (250-257) for the synthesis of I-substituted4-(N-arylalkanoamido)piperidines and relatives (Scheme 7-8) involve re-duction of a Schiff base (159), obtained by condensation of an anilinederivative with a l-substituted-4-piperidone, followed by acylation of the4-anilino intermediate (160). N-substituted derivatives are alternativelyobtained through a N-I-carbethoxy intermediate or the l-H piperidine,easily formed by catalytic hydrogenation of the l-benzyl-4-anilide. Whenthese sequences have been unsuccessful, for example, when the piperidinering is disubstituted or the aryl ring is peculiarly substituted, particularmodifications have been described. Various routes to the prototypiccompound, fentanyl (161), have also been reported (258-260).

5 5H, COZR, COR where R = R, NR'R"OH, OR, halogen,alkyl

~ )x

H, alkyl, or oxygenfunctionality: COZR,CHZOR, COR, DeOR

H, alkyl

C H ~ tI 1,2,3/n 2n

N11R

Fig. 7-J.

H, alkyl, aralkyl, heteroalkyl

Structural modification of 4-anilinopiperidine analgesics.

l

VI Anilino Family 363

a

159

1

b "'" BH~

X

NH4

c(

A.y J A"""';/eO~

Ac)' I 0010>;"-'160161

R1 = (CHZ) ZC6HS'Z 3

X = R = H, R = CZHS

Scheme 7-8. Synthesis of 4-anilino and 4-anilidopiperidines. Reagents: (a) p-TSA orZnCI,; (b) NaSH,; (e) (R'CO),O or R'COCI.

B. Structure-Activity Relationships: Generation of Compounds withClinical Utility

Interest in the family prototype (161, fentanyl), l-phenylethyl-4-(N-phenylpropionamido )piperidine, has stemmed from its extremely po-tent analgesic activity relative to other piperidine analgesics (Table 7-14).Fentanyl has almost 500 times the potency of meperidine (in mice,subcutaneously) and 220 times that of morphine (in mice, intraperitoneally)in the hot plate assay, and 500 times that of morphine in the rat tailwithdrawal protocol (intravenously) (261-263). The structure-activityrelationships of fentanyl analogs and 3-methyl derivatives demonstrate the


Table 7-14

Potencies of Piperidine Analgesics

Piperidine Analog Relative potency",b

Meperidine (4)

Bemidone (43)Alphaprodine (92)

Betaprodine (93)

Ketobemidone (47)Fentanyl (161)

11.57

3510

470

a Mice. subcutaneously.b References 34, 176,261.

following:

1. The significance of N-phenylethyl and N-propionyl groups in oplimiz-ing analgesic activity (261): alkyl, other aralkyl, and alkyl aminogroups on N-l are weaker or inactive; ethoxycarbonyl or hydrogen onthe aniline nitrogen diminish activity.

2. The necessity of an unsubstituted phenyl ring to maximize receptorbinding (264,265): phenolic hydroxyl and methoxyl derivatives(equivalents of the A-ring of morphine opiates) and rigid analogs areinferior, as measured by stereospecific binding with tritiated fentanylin rat brain homogenates.

3. The relationship of stereochemistry and configuration to potency(261,262,266-268): only small alkyl groups (i.e., methyl), exclusivelyat C-3, cis to the 4-anilido substituent and as the (+ )-enantlOmer,enhance activity [cis-3-methyl racemate 6 times, as the (-)-enantiomer 0.2 times, but as the (+ )-enantiomer 19 times the potencyof fentanyl, with (+ )-cis up to 6684 times the potency of morphine(rat tail withdrawal assay, intravenously)].

4. The geometry requirements in terms of anilino nitrogen to piperidinenitrogen distance (267): isofentanyl (162) suffers a 300-fold loss inanalgesic activity.

162

VI Anilino Family 365

5. The good correlation (a) between the in vitro affinity for the opiatereceptor and the in vivo analgesic potency and (b) between durationof fixation to the receptor sites and duration of action (269).

Fenta~Yl (Sublimaze, Leptanal) has been extensively studied since itsintroduction into clinical practice in the 1960s (270), and its pharmacokine-tic profile has been determined using radioimmunoassay techniques onsurgical patients (271,272). Due to a potency 50-100 times that ofmorphine, a '~apid onset of action, and a short duration, fentanyl's clinicalutility in surgical anesthesia is widespread, especially in combination withthe major tranquilizer droperidol (Innovan, Droleptan, Thalamontal) usedin a procedure called neuroleptanalgesia. A 0.2-mg dose of fentanyl isequianalgesic with 10 mg morphine, given intramuscularly. Unfortunately,fentanyl causes the expected morphine-like side effects. Studies with fJ.andS opiate receptors have shown that fentanylisothiocyanate (FIT) is a highlyselective alkylator of S receptors in brain membranes (273), and that3-methylfentanylisothiocyanate (super-FIT), an even more potent S opiatereceptor selective affinity ligand, can be used to purify the S receptorsubunit (297). (+ )-Cis-3-methylfentanyl (163), whose analgesic action isalso more rapid and has a shorter duration than morphine, is of interestclinically due to its lower toxicity (274).

XCOC2HS)-@

l.)CH3

NI

(CH2) 2C6HS

163

Exploration (275-277) of oxygenated substituents replacing hydrogen atC-4, and their C-3-,methyl counterparts, has led to the discovery of novelclinical agents of the fentanyl type with additional beneficial analgesicproperties, such as a shorter duration of action and a higher margin ofsafety. A small polar group at C-4 of the anilidopiperidines, that is,C-4-carboalkoxy, as in the meperidine family, C-4-alkoxymethyl orC-4-oxoalkyl, as in ketobemidone, significantly enhances the analgesicpotency relative to fentanyl. Structure-activity profiles found in fentanylitself also apply to these derivatives, for example, potency-enhancingsubstituents on the piperidine nitrogen (Table 7-15). Sufentanil (170)(278-280) and alfentanil (174) (281-283) are the most promising candi-dates for accepted clinical use in the United States, although other analogs,such as 169 (284) and carfentanil (164) (285), are being studied in the clinic(286).

R R' R' X Potency Ratioa,b

- 164 C,H,(CH2){ C02C11) C,H, H 7682165 C,H,S(CH,)," C02C113 CzHs H 7159166 C,H,(CH,Jz C02CI13 c-C)Hst H 6176

k"'""r..i

~167 C,H,CH,CH(CH,) C02CH3 C,H, H~~~-:;1r~ ';h( )

168 C,H,(CH,Jz C02CH3 CzHs 4-F~169 C,H,(CH,Jz" CH,OCH, C,H, H 4038 -f"ih.)

-170 C4H)S(CHzhC CH,OCH, C,H, H 3987171 C,H,(CH,Jz COCH, C,H, H 4921172 C,H,(CH,Jz COCH, c-C3Hs H 3795173 C,H,S(CH,Jz COC,H, C,H, H 4436161 C.H,(CH,h' H C,H, H 292

Morphine 1Meperidine 0.53


Table 7-15

Analgesic Activities of 4-Anilidopiperidinesx

(I

Reference 275.b Tail withdrawal, rats, intravenously.

" Clinical utility.d 2-Thienylethyl.

" Cyclopropyl.f

Fentanyl.

174

C. Rigid Analogs and Conformational Exploration

Attempts have been made to discover the relationships between theanilinopiperidines and the arylpiperidines or other analgesic agonists-antagonists with respect to conformational (structural) and stereochemical

References 367

criteria that determine binding to Ihe opiate receplor (287,288)_ Thesehave focused on the structure-activity relationships of rigid fentanyl-typeanalogs and determination of the absolute configuration of the more potentresolved 3ialkyl enantiomers. Ring expansion to perhydroazepines or ringcontractiop to pyrrolidines has shown that ring size does not significantlyalter the level of analgesic potency found for a beneficial combination ofsubstituents in the 4-(propananilido )piperidines (289). Whereas theobserved analgesic activity does not differ significantly in ring homologs, itis severely \diminished or abolished in analogs with conformational res-traints (29q-294). Isomeric N-substituted 3-(propanilido)nortropanes,stereochemi~ally a set of semirigid analogs, have shown that 3{3isomersare more potent than 3" (295). The potent (+ )-cis 3-methylfentanyl andits isothiocya,nate (super-FIT), both related to the more active (+ )-cis-{3-prodine antipode (35,45), have been assigned an absolute configurationof 3R,45 by recent X-ray analyses (298)_

o

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'i

~

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J68 7 Piperidine Analgesics

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(1981); 7,129,908 (1982).225. A. Hedges, P. Turner, and l. Wadsworth, Br. J. Anesthesiol. 52,295 (1980).226. A. G. Wade and P. J. Ward, l. Int. Med. Res. 10, 104 (1982); R. K. J. Price

and A. N. Latham, ibid. 10,219 (1982); e. E. Parker and A. F. Langrick, ibid. 10,408(1982).

227. C. V. Winder,M. Welford,l.Max,andD. W. Kaump,l. Pharmacol. Exp. Ther.154, 161(1966).

228. I. M. Lockhart,N. E. Webb,M. Wright,e. V. Winder,andP. Varner,l. Med. Chem.15,930 (1972).


229. I. M. Lockhart,N. E. Webb,M. Wright, C. V. Winder, and M. A. Hare,J. Med. Chern.15,687 (1972).

230. R. E. Bowman, H. O. J. Collier, P. J. Hattersley, I. M. Lockhart, D. J. PetersC. Schneider, N. E. Webb, and M. Wright, J. Med. Chern. 16,1177 (1973). '

231. R. E. Bowman, H. O. J. Collier, I. M. Lockhart, C. Schneider, N. E. Webb, andM. Wright,J. Med. Chern. 16, 1181 (1973).

232. M. J. Kamet and H. S. t. Tan,i. Pharm. Sci. 61, 188, 1936 (1972).233. D. C. Bishop,J. F. Cavalla, I. M. Lockhart, M. Wright, C. V. Winder, A. Wong, andM.

Stephens.J. Med. Chern. 11,1077 (1968).234. J. W. Epstein, H. J. Brabander, W. J. Fanshawe. C. M. Hofmann, T. C. McKenzie,

S. R. Safir, A. C. Osterberg, D. B. Cosulich, and F. M. Lovell, J. Med. Chern. 24,481(1981).

235. A. U. Epstein, A. C. Osterberg, and B. A. Regan, NIDA Res. Mongr. Ser. 41, 93(1982).

236. E. J. B. Porter, M. Rolfe, H. J. McQuay, R. A. Moore, and R. E. S. Bullingham, CurroTher. Res. 30, 156 (1981).

237. T. C. McKenzie, J. W. Epstein, W. J. Fanshawe, J. S. Dixon, A. C. Osterberg, L. P.Wennogle, B. A. Regan, M. S. Abel, and L. R. Meyerson, J. Med. Chern. 27, 628(1984).

238. P. A. Crooks and R. Szyndler, J. Med. Chern. 23, 679 (1980).239. H. Awaya, E. L. May, M. D. Aceto, H. Merz, M. E. Rogers, and L. S. Harris,J. Med.

Chern. 27, 536 (1984).240. D. M. Zimmerman, U. S. Patent 4,278,797 (July 14, 1981); Chem. Abstr. 94,83962

(1981).241. H. H. Ong, T. Oh-ishi, and E. L. May, J. Med. Chern. 17, 133 (1974).242. M. D. Aceto, L. S. Harris, and E. L. May, NIDA Res. Monogr. Ser. 41, 338 (1982).243. H. H. Ong, V. B. Anderson, and J. C. Wilker, J. Med. Chern. 21, 758 (1978).244. H. H. Ong, V. B. Anderson, J. C. Wilker, T. C. Spaulding, and L. R. Meyerson,

J. Med. Chern. 23, 726 (1980).245. M. Takeda, H. Inoue, K. Noguchi, Y. Honma, M. Kawamori, G. Tsukamoto,

Y. Yamawaki, S. Saito, K. Aoe, T. Date, S. Nurimoto, and G. Hayashi, J. Med. Chern.20, 221 (1977).

246. T. G. Cochran, J. Med. Chern. 17, 987 (1974).247. G. Hite, P. Salve, J. B. Anderson, M. Rapposch, M. Mangion, and M. Froimowitz,

Acta Crystallogr., Sect. B. 40, 850 (1984).248. T. R. Burke, Jr., A. E. Jacobson, D. C. Rice, and J. V. Silverton, J. Org. Chern. 49.

1051 (1984).

249. T. R. Burke, Jr., A. E. Jacobson, K. C. Rive, and J. V. Silverton, J. Org. Chern. 49,2508 (1984).

250. P. A. J. Janssen, U. S. Patent 3,141,823 (July21, 1964); Chern. Abstr. 62, 14634 (1965).251. C. Janssen, Fr. Patent 1,517,671 (March 22, 1968); Chern. Abstr. 70, 115015 (1969).252. J. W. Cole and R. Hallas, U. S. Patent 3,686,187 (August 22,1972); Chern. Abstr. 77,

139823 (1972).253. P. A. Janssen and G. H. P. Van Daele, Ger, Offen. 2,610,228 (September 3D, 1976);

Chern. Abstr. 86, 29645 (1977).254. P. A. J. Janssen and G. H. P. Van Daele, U. S. Patent 4,179,569 (December 18,1979);

Chern. Abstr. 92, 128743 (1980).255. R. S. Vartanyan, V. O. Martirosyan, E. V. Vlasenko, L. K. Durgaryan, and A. S.

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~

57' R.-S. Zong, D.-X. Yin, and R.-Y. Ji, Yao Hsueh H!>ueh Pao 14, 362 (1979).\s 258. S.-H. Zee, C.-L. Lai, Y.-M. Wu, and G.-S. Chen, K'o Hsueh Fa Chan Yueh K'an 9, 387

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259. S.-H. Zee and W.-K. Wang, J. Chin. Chem. Soc. (Taipei) 27, 147 (1980).260. A. Jonczyk, M. Jawdosiuk, M. Makosza, and J. Czyzewski, Przem. Chern. 57, 131

(1978).261. A. F. Casy, M. M. A. Hassan, A. B. Simmonds, and D. Staniforth, J. Pharm.

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1047 (1974).263. W. Jin, H. Xu, Y. Zhu, S. Fang, X. Xia, Z. Huang, B. Ge, and Z. Chi, Sci. Sin. (Engl.

Ed.) 24, 5 (1981).c;64. M. W. LobbezoQ, W. Soudijn, and I. van Wijndaarden,J. Med. Chern.24,777 (1981);-./ M. w. Lobbezoo, W. Soudijn, and I. van Wijngaarden, Eur. J. Med. Chern. 15,357

(1980). \265. M. W. Lobbezoo, W. Soudijn, and I. van Wijnaarden, EUr. J. Med. Chern. Chirn. Ther.

4, 357 (1980). '266. A. F. Casy and F. O. Ogungbamila, Eur. J. Med. Chern. Chirn. Ther. 18, 56 (1983).267. T. N. Riley, D. B. Hale, and M. C. Wilson, J. Pharm. Sci. 62, 983 (1973).268. P. A. Janssen, W. F. M. Stokbroekx, and A. Raymond, U. S. Patent 3,907,813 and

3,907,811 (September 23, 1975); Chern. Abstr. 84, 4821 (1976).269. J. E. Leysen and P. M. Laduron, Arch. Int. Pharrnacodyn. 232, 243 (1978).270. J. S. Finch and T. J. Kornfeld, J. Clin. Pharmacol. 7,46 (1967).271. R. Schleimer, E. Benjamini, J. Eisele, and G. Henderson, Clin. Pharmacal. Ther. 23,

188 (1978).272. C. C. Hug. Jr., "The Pharmacokinetics of Fentanyl." Janssen Pharmaceutica, Inc.,

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~

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C-3-1,M..(-40,,>,~"~.!,.

3767 Piperiqine Analgesics

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press, 1986).

8.

Physical Chemistry, Molecular Modeling, andQSAR Analysis of the Arylpiperidine Analgesics

l. Physico~hemicalStudies .

A. X-Ray CrystallographyB. Protdn NMR . .C. Carbdn-13 NMR . . . . . . . . . . . . . . . .

II. Stereostructure, Conformation. and Biological Activity .......III. Molecular Modeling and Ouantitative Structure-Activity Relationship

(QSAR) Studies ...

A. Molecular'ModelingB. OSAR Studies.References

.

377378380383385

388388394398

1. Physicochemical Studies.

Embedded in Ihe struclure of morphine is a piperidine ring in a chairconformation, with an axial phenyl ring bonded at the 4-position (Fig. 8-1).This was recognized early on and was postulated to be a key pharma-cophore. Since the late 1940s, numerous 4-phenylpiperidine-based analge-sics have been synthesized and lested (for reviews, see references 1 and 2).Intereslingly, however, most of the active compounds in this series are notexpected to exist in a phenyl-axial conformation to any significant extent.Conformation and stereostructure-activity relationships in this series areof further interest because the molecule is prochiral; substitution on thepiperidine ring renders the 4-position optically active, and stereoseleclivilyis observed in the biological activities of these compounds. The two sides ofthe piperidine ring may be labeled pro-4R and pro-4S, as shown in Fig. 8-2.Numerous 3-alkyl derivalives and all possible mono- and dimethyl deriva-tives have been synthesized and studied. X-Ray crystallography andnuclear magnetic resonance (NMR) speclroscopy have played key roles in

HO'"Fig. 8-1. Morphine structure, highlighting the embedded 4-phenylpiperidine fragment.

377

378 8 Physical Chemistry, Molecular Modeling, QSAR of Arylpiperidine Analgesics

o ~N-CHJ

~'O_4!1COOEt

Fig. 8-2. Meperidine structure, showing the pro-4R and pro-4S edges of the piperidinering (after Portoghese, reference 2).

elucidating the relationships between molecular configurations, conforma-tions, and biological activities in this class of aryl piperidine analgesics.(Note: Some of the early literature dealing with 1,2,5-trimethylpiperidinederivatives has discrepancies in usage of the terms a, /3, y,o. Reference 1clarifies these ambiguities and should be consulted when reading theliterature on these compounds.)

The next three sections describe the application of crystallography,proton NMR, and carbon-13 NMR to the characterization of arylpipcri-dine analgesics. The following section focuses on stereostructure, con-formation, and analgesic activity, in which the results of all of thesemethods are integrated and interpreted in terms of the observed biologicalactivities.

A. X-Ray Crystallography

Crystallographic studies have contributed substantially to an under-standing of the steric requirements for receptor binding of arylpiperidines.Table 8-1 lists the compounds whose structures have been determined

Table 8-1

X-Ray Crystallographic Studies of Arylpiperidine Analgesics

Compound Conformation Reference

Meperidine (I)

a-Peadine (2)

{J-Prodine (3)

a-Allylprodine (4)

{J-Attylprodine (5)

{3-1,2-Dirnethyl-4-phenyl-4-propionyloxypipcridine (6)

a-l,2,3- Trimethyl-4-phenyl-4-piperidinol (7)

{3-1,2,3- Trimethyl-4-phenyl-4-piperidinol (8)

y-l ,2,3- Trimcthyl-4-phenyl-4-piperidinol (9)

a-I ,2,5- Trimethyl-4-phenyl-4-piperidinol (1 o)ay-l,2,5- Trimethyl-4-phenyl-4-piperidinol (11)1,2,6- Trimcthyl-4-phenyl-4-acetoxypiperidine (12)

y-I,3 ,5- Trimethyl-4-phenyl-4-propionoxypiperidine (13)

Chair phenyl-equatorial









Chair phenyl-axial

Chair phenyl-equatorialChair phenyl-equatorial


34566788899

1111

a Reference 9 incorrectly labels the a-isomer as the ,B-isomcr. See reference J for corrected structures

in this series.

\I

1


crystallographically. The conformation of the piperidine ring in the solidstate is also reported in Table 8-1. In some cases, the structure studied hasbeen the parent alcohol rather than the biologically active ester. Casy haspresented reasons for assuming that the alcohol and ester will possesssimilar solid-state conformations in most cases (12). The solid-stateconformation of the piperidine ring is a chair for all compounds. Only oneof these compounds (10) has an axial phenyl substituent. Among the threeisomeric 2,5-dimethyl-piperidines, this isomer is the most potent analgesic.

caDEt

1 meperidine

'[(0o

3 {3 -prodine

/f(0o

5 {3 -allyl prodine

7 R::: H. Ac

2 c2 -prod ine

-"')(0o

4 a -allyl prodine

OR

6 R = H, COEt

OR

8 R'"

H, Ac

Table 8.2

Proton NMR Studies of Arylpiperidine Analgesics

Compound State Solvent Conformation(s) References

a-Prodine-alcohol (2) Base COCl, Chair phenyl-equatorial 14HCI COCl, Chair phenyl-equatorial 14

" HCI 0,0 Chair phenyl-equatorial 14p-Prodine-alcohol (3) Base COCl, Chair phenyl-equatorial /4

HCI COCI, Chair phenyl-equatorial 14HCI 0,0 Chair phenyl-axial" 14

It" a-Prodine (2) HCI COCl, 100% chair phenyl-equatorial /2

/3-Prodine (3) \ HCI 0,0 Chair phenyl-equatorial /2HCI COCl, 75-80% chair phenyl-equatorial /2HCI 0,0 Twist-boat (14)" /2

a-Aliylprodine (4)'0"

HCI COCI, Chair phenyl-equatorial /5,16/3-Aliylprodine (5)

'0"HCI COCl, Chair phenyl-equatorial /5,/6

a-2-Methyl-alcohol (IS) Base COCl, Twist-boat (15) and/or chair, /7phenyl-equatorial

HCI OMSO Twist-boat (15) and/or chair, /7phenyl-equatorial; epimericconjugate acids

/3-2-Methyl-alcohol (6) Base COCl, Chair phenyl-equatorial 17HCI OMSO Chair phenyl-equatorial 17

a-2-Methylpropionyl Base COCI, Chair, phenyl-axial 17ester (IS) HCI COCI, Chairs 17

phenyl-axial + phenyl-equatorial 2 : I, epimericconjugate acids

11-2-Methylpropionyl Base COCl, Chair phenyl-equatorial /7ester (6) HCI COCl, Chair phenyl-equatorial /7

a-I,2,3-Trimethyl-4- Base COCl, Chair phenyl-equatorial /8phenyl-4-piperidinol (7)

/3-1,2,3- Trimethyl-4- Base COCl, Chair phenyl-equatorial /8phenyl-4-piperidinol (8)

')'-1,2,3- Trimethyl-4- Base COCl, Chair phenyl-equatorial 18phenyl-4-piperidinol (9)

')'-1,2,3-Trimethyl-4- Base CCI, Twist-boat (16) /8phenyl-4-piperidinol (9)

a-I,2,3- Trimethyl-4- HCI COCl, Chair phenyl-equatorial /8phenyl-4-propionyloxy-piperidine (7)

/3-1,2,3-Trimethyl-4- HCI COCl, Chair phenyl-equatorial 18phenyl-4-propionyloxy-piperidine (8)

1"1,2.3- Trimethyl-4- HCI COCl, Chair phenyl-equatorial /8phenyl-4-propionyloxy-piperidine (9)

')'-I,2,3-Trimethyl-4- HCI 0,0 Chair phenyl-equatorial /8phenyl-4-propionyloxy-piperidine (9)

(continued)

.380 8 Physical Chemistry, Molecular Modeling, QSAR of Arylpiperidine -Analgesics

9 R = H, Ac10

OH

1112

13

B. Proton NMR

Since proton-proton coupling constants for vicinal protons are depen-dent on the torsional angles between the protons, proton NMR isparticularly well suited to studying the conformations of six-membered ringcompounds (for example, see reference 13). Thus, it is not surprising thatmany papers have appeared in which the solution conformation(s) ofarylpiperidine analgesics have been examined by this method. ProtonNMR studies of these compounds are summarized in Table 8-2. It isimportant to note that the solvent, the presence or absence of the estergroup, and the state of the basic nitrogen atom all influence the results. Forinstance, the 2,3-dimethylpiperidine isomer, 9, was found to exist in aphenyl-equatorial chair conformation with both methyl groups axial in thesolid state (8) and, under most conditions, in solution (18). However, theparent alcohol in dilute solution in CCl. exists in the boat form 16, due tothe intramolecular hydrogen bond shown. It is tempting to assume that the

\

1

Table 8-2 (Cont.)

Compound State Solvent Conformation(s) References

a-l.2,5- Trimelhyl-4- Base COo., Chair phenyl-axial /9phenylpiperidinol (10)

(j-l,2.5-Trimcthyl-4- Base CDCll Chair phenyl-equatorial /9"phcnylpipcridinol (17)

y-t ,2,5- Trimethyl-4- Base CDC/_! Chair phenyl-equatorial /9phenylpiperidinol (II)

CIS.l,2.5-Trimethyl-4- Base CDCI, Chair phenyl-equatorial /9"phcnylpipcridinol (18)

4-Acctoxy-l,2.6- HCI CDCl) Chair phenyl-equatorial 20trimethyl-4-phenyl-piperidine (19)

4-Aceloxy-I,2.6- HCI. COo., Chair phenyl-equatorial 20trimethyl-4-phenyl-piperidine (20)

4-Acctoxy-I,2,6- HCI CDCI) Chair phenyl-axial 20trimethyl-4-phenyl-piperidine (21)

Tropane analog (22) HCI CDCl) Chair phenyl-axial 2/


a Casy et at. initially interpreted the proton NMR spectra of these compounds in terms ofphenyl.axial-chair and twist-hoat conformations (12). Later, they considered these compounds to be

in phenyl-equatorial chair conformations on the basis of carbon.13 NMR spectra (15).h Reference 19 has the lahels {3 and () interchanged; see reference 1 for corrected structural

assignments.

14 .B-prodine, twist-boatconformation

15 R H, COEt 16


17 18

OAeOAe

19 20

21 22

conformation in aqueous solution is most relevant to the biological activity,but the degree of solvation and the hydrophobicity of the receptor bindingsite are not yet known. In addition, drug receptor interactions could affectthe receptor-bound conformation. Thus, it is necessary to take intoconsideration all of the observed conformer states in assessing structure-activity relationships.

C. Carbon-I3 NMR

Jones and co-workers interpreted the carbon-13 NMR spectra of the 1,2-and 1,3-dimethylpiperidine compounds (IS, 6, 2, and 3) in terms of theirconformations as previously derived from proton NMR and X-ray crystal-lography (22). From these compounds and a few simpler model com-pounds, they derived a set of additivity parameters for the piperidine ring


carbon resonances. They then used these parameters to interpret thecarbon-13 NMR spectra of several 1,2,5-trimethylpiperidine compounds(10, II, and 17) in terms of their configurations and conformations (23).(As described previously, reference I should be consulted for correctedusage of the terms a, (3, y, and 8 in this series.) Jones et al. (22) concludedthat the a-isomer is in a chair conformation with the phenyl axial, asdepicted in 10. They interpreted the spectrum of the {3-isomer (17) in termsof a twist-boat conformation, as shown in 23. The y-isomer was projectedto have a chair conformation with the phenyl group equatorial, as shownforIl.

OR

/23 R ""

H, COEt

OCOEt

24

OAe

25

The same approach was used by Casy and co-workers in determining thesolution conformations of the three isomeric 1,2,3-trimethyl derivatives 7,8, and 9 (/8). All three of these compounds (as the ester hydrochlorides inCOCI3) were concluded to exist in phenyl-equatorial chair conformations,even though this forces both methyl groups to occupy axial positions in y-isomer 9.

/

L

II Stereostructure, Conformation, and Biological Activity 385

II. Stereostructure, Conformation, andBiological Activity,

Meperidine (I) and the 3-alkyl compounds 2-5 all exist in the solid stateand in solution in a phenyl-equatorial chair conformation. Placing a 3-alkyl(methyl, ethyl, propyl) equatorial substituent on the pro-4S edge of thepiperidine ring has essentially no effect on analgesic activity, while a 3-alkylequatorial substituent on the pro-4R edge of the ring results in a substantialdecrease in activity. 3-Alkyl axial substituents produce a slight decrease inactivity on the pro-4R edge of the ring and an increase in activity on thepro-4S edge of the ring. The 3-allyl substituent behaves differently fromsimple alkyl (including n-propyl) substituents; the allyl derivatives aresubstantially more active than the unsubstituted parent compound, sug-gesting a specific nonsteric interaction with the receptor (6,24).

The a-2-alkyl compound 15 is conformationally mobile in solution (/7).The parent alcohol (both the hydrochloride and the base) appears to existas a mixture of the twist-boat form shown in structure 15 and thephenyl-equatorial chair; the hydrochloride also appears to be a mixture ofthe epimeric conjugate acids in which either the N-methyl group or theproton may be equatorial. The twist-boat form can be stabilized byintramolecular hydrogen bonding. Esters of 15 in COCl, solution are in thephenyl-axial chair conformation (base) or in a 2:1 mixture of the phenyl-axial chair and phenyl-equatorial chair forms. The racemic mixture hasapproximately the same analgesic activity as the parent compound with no2-substituent. In view of the conformational flexibility of this compound, itis difficult to draw conclusions about its specific receptor requirements.

The {3-2-methyl compound 6 is in a phenyl-equatorial chair conformationwith the 2-methyl group in an equatorial position both in the solid state (7)and in solution. (/7). When the methyl group is on the pro-4R edge, thecompound is as active as the desmethyl parent; the 4S isomer showsdecreased activity, suggesting steric interference with receptor binding.

The esters of all four of the 2,3-dimethyl compounds (7, 8, 9 and 24)appear to favor the phenyl-equatorial chair conformation, on the basis ofX-ray crystallographic, proton NMR, and carbon-13 NMR studies (8,/8).This finding is surprising only in the case of y-isomer 8, in which bothmethyl groups are in axial positions. The parent alcohol of this isomer inCCl4 solution can adopt a twist-boat conformation, stabilized by anintramolecular hydrogen bond (16), but the esters show no such tendency.The {3-isomer, 8, has both methyl groups in equatorial positions. Based onthe findings that a pro-4R-equatorial 3-methyl group or a pro-4S-equatorial 2-methyl group decreases analgesic activity, it could be expectedthat neither of the {3-isomers would show good analgesic activity; this isindeed the case. Similarly, 8-isomer 24 must have either an axial 3-methyl

386 8 Physical Chemistry, Molecular Modeling, OSAR of ArylpiperidiDc Analgesics

unfavorably placed on the pro-4R edge or an equatorial 2-methyl unfavor-ably placed on the pro-4S edge; the racemic mixture is inactive. Theracemic y-2,3-dimethyl compound 9 is slightly more active than thedesmethyl parent compound. As described above, this compound shouldhave the 2- and 3-methyl groups axial. Since an axial 3-methyl groupimproves activity on the pro-4S edge and diminishes activity on the pro-4Redge (see above), it follows that the axial 2-methyl group on the pro-4Sedge is sterically acceptable. This interpretation is further supported by thefinding that the tropane analog 2S (comparable to having 2,6-diaxialsubstituents) retains activity (25). The racemic a-isomer has activity nearthat of the desmethyl compound. Most of the activity is expected to residein the compound having the methyl groups on the pro-4S edge, sinceneither the 2-axial nor the 3-equatorial methyl should interfere withbinding. On the pro-4R edge, the 3-equatorial methyl group was previ-ously shown to decrease activity (see above).

All four of the 2,5-dimethyl compounds (the promedols, 10, 11, 17, and18) have been studied by NMR spectroscopy (19,23). In addition, two ofthe structures have been determined crystallographically (9). (See refer-ence 1 regarding discrepanci~ in the nomenclature of these compounds inthe literature.) The a-isomer, 10, is one of the few compounds in which anaxial phenyl group is apparently favored, since it puts both of the methylgroups in equatorial rather than axial positions. For the a-isomer, analge-sic activity resides in the enantiomer with the equatorial 2-methyl group onthe pro-4S edge and the 5-methyl group in the pro-4R edge; the otherenantiomer is inactive. The remaining isomers, 11, 17, and 18, allpreferentially adopt the phenyl-equatorial chair conformation. The race-mic f3-isomer, 17, is as active as the desmethyl parent. On the basis of thediscussion above, it is expected that the activity originates in the isomerhaving the axial 2-methyl on the pro-4R edge and the equatorial 5-methylon the pro-4S edge. The y-isomer 11 has been resolved into its enantio-mers. When the equatorial 2-methyl is on the pro-4R edge and theequatorial 5-methyl is on the pro-4S edge, the analgesic activity isequivalent to that of the desmethyl parent. In this case, both methyl groupsare in sterically acceptable positions, as described above. Conversely, if theequatorial 2-methyl is on the pro-4S edge and the equatorial5-methyl is onthe pro-4R edge, both substituents are in unfavorable positions, and thiscompound is substantially less active. Finally, the racemic o..isomer 18shows good analgesic activity. Again, the analgesic activity is expected tocome from the enantiomer having the equatorial 2-methyl group on thepro-4R edge and the axial 5-methyl group on the pro-4S edge. The otherenantiomer of this compound will have both methyl substituents inunfavorable positions, as described above.

II Stcrcostructure, Conformation, and Biological Activity387

There are three possible isomers (19, 20, and 21) in the 2,6-dimethylseries. Each of these has been studied by proton NMR (20), and one hasbeen examined crystallographically (10). The first two compounds are inphenyl-equatorial chair conformations. Racemic 19 is more active than thedesmethyl compound. When the equatorial methyl group is on the pro-4Sedge, it is expected to interfere with biological activity, so the activityshould reside primarily in the compound having an equatorial methylgroup on the pro-4R e.dge and an axial methyl group on the pro-4S edge.Compound 20 has an equatorial methyl group on the pro-4S edge and wasfound to be inactive. Like compound 20, isomer 21 has two equatorialmethyl groups. In 21, the phenyl group is axial. This compound is alsoinactive as an analgesic.

Among the three isomeric 3,5-dimethyl compounds, only one shows anyactivity: isomer 13 (11). A crystallographic study showed that this com-pound is in the usual phenyl-equatorial chair conformation. The less activeisomer has an axial methyl unfavorably placed on the pro-4R edge; themore active isomer has an equatorial methyl unfavorably placed on thepro-4R, but it has an axial methyl group on the pro-4S edge, which wasshown to increase analgesic activity (see above).

The results for the phenyl-equatorial compounds are summarized in Fig.8-3. On the pro-4R edge of the piperidine ring, substitution on the2-position is acceptable, while 3-substituents decrease activity. On thepro-4S edge, substitution is acceptable on the 3-position and on the 2-axialposition; 2-equatorial substitution leads to decreased activity. The data areless extensive for the phenyl-axial compounds. Figure 8-4 summarizes theresults determined to date. On the pro-4S edge of the ring, a 2-equatorialsubstituent decreases activity, while 2-axial and 3-equatorial substituentshave no effect. Both axial and equatorial substituents are acceptable on the2-position of the pro-4R edge, but pro-4R 3-equatorial substitution de-creases activity.

X-ray crystallographic studies have revealed another structural featurethat correlates with analgesic activity (2,Il). The more active enantiomers

. Fig. 8.3. Summary of structure-activity relationships for methyl-substituted phenyl-equatorial-chair piperidines. 0, no effect on activity; @, decreased activity; ([Y, increasedactivity.

Relative RelativePotencyh Energy Concentration

ED.'\(I after Brain Difference, of Analgesic(mgjkg) Penetration kcal/mole Conformation

3-Demethylprodine 1.00 1.00 0.0 1.00(3R,4S)-a-Prodine 1.45 1.24 0.5 1.40(3S,4S).fJ.Prodine 5.2t 1.77 3.7 2.00

388 8 Physical Chemistry, Molecular Modeling, QSAR of Arylpiperidip.e Analgesics

Fig. 8.4. Summary of structure-activity relationships for methyl-substituted phenyl-axial-chair piperidines. Key as in Fig. 8-3.

IRIal R (bJ

Fig. 6-5. Rotation of the phenyl ring relative to the piperidine ring in ~a) mo~e active and(b) less active isomers of arylpiperidine analgesics in the phenyl-equatonal chaiT configura-

tion. See Reference 2 for details.

are those in which the phenyl ring is in the conformation shown in Fig.8-5a and the less active enantiomers are as shown in Fig. 8-5b. This,

"conformational feature is controlled by the presence or absence ofsubstituents in the 3- and 5-positions of the piperidine ring.

III. Molecular Modeling and Quantitative Structure-Activity Relationship (QSAR) Studies

A. Molecular Modeling

Froimowitz (26) has carried out a conformational study of variousphenylpiperidine analgesics (the prodines, ketobemidone, meperidine,and 1,3,4-trimethyl-4-phenylpiperidines) using Allinger's molecular me-chanics program MM2 (27). Phenyl equatorial conformations were foundto be preferred for the prodines, ketobemidone, and meperidine. Thecalculated equatorial and axial phenyl conformations for the prodines areshown in Fig. 8-6. For ketobemidone and meperidine, however, phenylaxial conformations were computed to be only 0.7 and 0.6 kcal/mole,respectively, higher in energy. It was suggested that phenyl axial con-formers may be responsible for the potency-enhancing effect of a phenylmeta-hydroxy group in these two compounds.

In contrast, phenyl axial conformers were computed to be relativelyunfavorable for the prodines, being 1.9, 2.8, and 3.4 kcal/mole higher inenergy for 3-demethyl, a-, and j3-prodine, respectively. Froimowitz related

I~,.

III Molecular Modeling and QSAR StudiesJS9

a

c

Fig. 8-6. Lowest-energy phenyl equatorial and phenyl axial conformers for the prodines.Relative steric energies are (a) 10.5 and 12.4 kcal/mole for 3-demethylprodine, (b) 12.9 and15.7 kcal/mole for a-prodine, and (c) 13.2 and 16.6 kcal/mole for l3-prodine.

the relative concentrations of an analgesic conformation to the potencies ofthese three compounds (see Table 8-3).

A phenyl axial conformer was calculated to be preferred by 0.7kcal/mole for the 3-demethyl compound of 1,3,4-trimethyl-4-phenylpiperidine, with phenyl equatorial conformers preferred by 1.3 and

Table 8-3

Correlation of the Relative Potencies of 3-Demethylprodine, a-Prodine, and I3-Prodinewith the Relative Concentration of Their Analgesic Conformationa

a Differences in brain penetration have been adjusted for. Energy differences arebetween the two conformers that have identical energies when the piperidine ring does notcontain a substituent in the 3-position. The analgesic conformation is assumed to be the onethat is favored by a substitution on the pro-4S edge of the piperidine ring.

h Reference 28.

Drug ('" )-IHrodine (:t)-a-Prodinc DesmethyJprodine Meperidine

dE (eq-ax)" 21.0 8.6 6.6 5.3Potency (EDso) 0.32 1.7 1.3 13.t

390 8 Physical Chemistry, Molecular Modeling, QSAR of ArylpipcriQine Analgesics

3.3 kcal/mole for the a and {3compounds. Phenyl axial conformers wereunexpectedly found to be especially destabilized by a 3-methyl group in the(3 configuration due to the steric crowding of the three piperidine substi-tuents. Comparisons were also made between the computed structures andthose observed by X-ray crystallography (4,5).

More recently, Froimowitz and Kollman (29) carried out additionalconformational energy calculations on various prodine derivatives usingboth MM2 (molecular mechanics) and the semiempirical quantum mecha-nical (PClLO) methods. Compounds studied include 3-demethylprodine,a-prodine, {3-prodine, the a-2-methyl derivative, a-promedol, the y-2,3-dimethyl derivative, and y-isopromedol. All of the compounds arepredicted to activate the opiate receptor in a phenyl equatorial conforma-tion. Optimum activity is postulated to result from a specific orientation ofthe phenyl and propionoxyl groups.

The a-promedol analog is calculated to be most stable in a phenylequatorial conformation which is in disagreement with experimental data.Two mirror-image phenyl equatorial conformers are preferred for 3-demethylprodine. The more active prodine antipodes consistently preferthe conformer in which the phenyl orientation is opposite to (i.e., themirror image of) that of mOrphine and the morphine-like (+ )_phenylmorphan. The authors suggest that this observation may be themolecular basis for the non-morphine-like behavior that arises with theintroduction of a phenyl meta-hydroxyl into some prodine analogs.

The findings of Froimowitz are qualitatively similar to those of Loew andJester (30), who also carried out PClLO calculations on meperidine andthe prodines. The energy differences between phenyl equatorial andphenyl axial conformers were found to increase in the order meperidine,3-demethylprodine, a-prodine, and {3-prodine. However, the energy dif-ferences are three to nine times greater according to the PClLO calcula-tions compared to the molecular mechanics results. This, however, may bea consequenc~ of Loew and Jester's failure to carry out a completestructure optimization.

Loew and Jester (30) also computed the charge distributions for thecompounds they studied and superimposed the minimum energy con-formers on an energy-optimized structure of morphine. Figure 8-7 illus-trates, for example, the minimum-energy conformer of meperidine super-imposed on morphine (dotted structure). The charge densities are alsoshown in Fig. 8-7.

A correlation between the calculated energy difference between equato-rial and axial energies and analgesic potency was observed for fourcompounds, as reported in Table 8-4.

III Molecular Modeling and OSAR Studies 391

+0.16H

+0.02 -0.05

.0.04+0.08

.0.02 +0.08.0.07

/,.-:0.02 +0.02

"/ \.0.02 { 0/'

~ 0.3...]";. ...": 0 :: -0.11:

I .0.17 J"- ,

"-0.02

Fig. 8.7. Minimum-energy conformer of meperidine with a piperidine ring superimposed

on that of morphine (pharmacophore I) and nct atomic charges.

Table 8-4

Relationship between Potency and Relative Axial Energies in Meperidine and Prodines

"ilE in kcalj molc.

In a set of analogs of the prodine analgesics, the energy of the highestoccupied molecular orbital of the aryl moiety correlates with the I?g ED50obtained from the mouse hot plate assay by subcutaneous admInIstratIOn(31). The orbital energies were not actually computed, but taken from adata table. Thus, there is a concern regarding the reliability of thesemeasures in the actual compounds of interest. Also, only six compoundshave been used to establish the correlation. Nevertheless, this observationsuggests a possible charge transfer interaction between the ~ryl groups ofthe analgesics and their receptors, wIth the aryl groups actIng as chargedonors. This model can and should be tested.

Isoelectrostatic contour spheres for morphine, meperidine, and a-prodine were constructed by Breon et al. (32) usin? quantum mechanics.Minor configurational changes were made In meperIdIne and a-prodIne toapproximate the spatial configuration of morphine, the most rigid analog

Table 8-50

Hot Plate Analgesic Potency and Physicochemical Parameters of Substituted Benzoic ACId Esters of l-Methyl-4-piperidinol'.ft})- ~o-GN-CH,

Rn

LogO/c)'No. R, h ~m ~o L" 81,m. FI.m Bl,pQ EJ,p HBo HBm HB, Obsd. Calcd.c .1 3,4-(OCH3h 0.08 0.04 0 0 0.35 -0.55 0.35 -0.55 0 1.128 1.128 1.91 1.84 0.072' 4-0C3H3 0.38 0 0 0 0 0 0.35 -0.62~ 0 0 1.248 1.72 1.61 0.113 3-0CH3 -0.02 -0.02 0 0 0.35 -0.55 0 0 0 1.128 0 1.67 1.63 0.044' 4-CN -0.57 0 0 0 0 0 0.6 -0.51 0 0 1.898 1.65 1.62 0.035 3,4.(OCH,O) -0.05 -0.025 0 0 0.2' -0.5V 0.2 -0.55 0 1.128 0 1.61 1.65 -0.046' 4-0-n-C~H9 1.55 0 0 0 0 0 0.35 -0.94' 0 0 1.248 1.58 1.56 0.027' 2,4,6-(CHJh 1.29 0 0.86 1.8B 0 0 0.52 -1.24 0 0 0 1.55 1.11 -0.448 2,3-(OCH3h 0.08 -0.02 -0.02 1.92 0.35 -0.55 0 0 1.128 1.128 0 1.55 1.49 0.069 3,5-(OCH3h 0.08 0.08 0 0 0.7 -1.1 0 0 0 1.128 0 1.53 1.43 0.10HI' 2-CF) 0.88 0 0.88 1.24 0 0 0 0 1.078 0 0 1.49 1.35 0.1411 2-CH) 0.56 0 0.56 0.94 0 0 0 0 0 0 0 1,48 1.37 0.1I12' 2-NO] -0.28 0 -0.28 1.38 0 0 0 0 1.918 0 0 1,48 1.34 0.1413 2,4,6-(OCH)h 0.06' 0 0.04 3.84 0 0 0.35 -0.55 0' 0 1.128 1.47 1.33 0.1414 H 0 0 0 0 0 0 0 0 0 0 0 1.43 1.44 -0.0115 4-0CH3 -0.02 0 0 0 0 0 0.35 -0.55 0 0 1.128 1.43 1.62 -0.1916 2-0CH) -0.02 0 -0.02 1.92 0 0 0 0 1.128 0 0 1.43 1.30 0.1317 2-F 0.14 0 0.14 0.59 0 0 0 0 0 0 0 f,41 1.40 0.0118 3-0CH),4-CH) 0.54 -0.02 0 0 0.35 -0.55 0.52 -1.24 0 1.128 0 1.4 1.44 -0.0419' 3-CN -0.57 -0.57 0 0 06 -0.51 0 0 0 1.898 0 1.39 1,48 -0.0920 4-F 0.]4 0.0 0 0 0 0 0.35 -0.46 0 0 0 1.38 1.37 0.0121 2,5-(CH)h 1.07k 0.56 0.56 0.94 0.52 -1.24 0 0 0 0 0 1.36 1.29 0.0722 3,4,5-(OCHJh -0.6 -0,4 0 0 0.7 -1.1 0.35 -0.55 0 1.128 1.128 1.35 1.36 -O.o.t23 3-F,4-CHJ 0.7 0.14 0 0 0.35 -0,46 0.52 -1.24 0 0 0 1.32 1.07 0.2524' 2.CH3C~H9 2.01 0 2.01 1.57 0 0 0 0 0 0 0 1.28 1.32 -0.0425 2,6-(CH]h 1.07 0 1.07 1.88 0 0 0 0 0 0 0 1.27 1.30 -0.0326 3-F 0.14 0.14 0 0 0.35 -0,46 0 0 0 0 0 1.26 1.26 0.0027' 2.CI 0.71 0 0.71 1.46 0 0 0 0 0 0 0 1.25 1.33 -0.0828 3.0H -0.67 -0.67 0 0 0.35 -0.55 0 0 0 1.0 0 1.2J 1.24 -0.03

~''';{''toot'

"I29' 2-Br 0,86 0 0.86 1.77 0 0 0 0 0 0 0 1.21 1.31 -0.1030 4-CH) 0.56 0 0 0 0 0 0.52 -1.24 0 0 0 1.17 1.25 -0.0831 2,4,5-(CH)) 1.5 0.56 0.56 0.94 0.52 -1.24 0.52 -1.24 0 0

/ !918

1.17 1.10 0.07324.11 4-NO] -0.28 0 0 0 0 0 0.7 -2.52 0 0 1.14 1.31 -0.0733 4-C(CH3h 1.98 0 0 0 0 0 1.59 -2.78 0 0 1.13 1.01 0.1234' 4-CI 0.71 0 0 0 0 0 0.8 -0.97 0 0 0 1.11 1.29 -0.1835 3,4-CIJ 1.25 0.71 0 0 0.8 -0.97 0.8 -0.97 0 0 0 1.08 1.08 0.0036 3,5-(CHJ)3 1.07 0.107 0 0 1.04 -2,48 0 0 0 V 0 1.07 1.25 -0.1837' 4-CJ19 1.96 0 0 0 0 0 2.11/ -3.82/ 0 0 0.85 0.85 0.0038' 2,6-(OCH)h 0.08 0 0.08 3.84 0 0 0 0 Of 0 0 0.63 1.15 -0.5239"'.11 2-Cr.H9 1.96 0 1.96 4.22 0 0 0 0 0 0 0 1.52' 1.12 DAD40 2-0C6H9 2.08 0 2.08 2A5 0 0 0 0 0- 0 0 1.24" 1.26 -0.0241 2-0C)H9 0.38 0 0.38 2.86 0 0 0 0 1.248 0 0 1.18" 1.23 -0.0542' 2.CzH9 1.02 0 1.02 2.05 0 0 0 0 0 0 0 1.15" 1.29 -0.1443 3,4-(CHJ)3 0.99 0.56 0 0 0.52 -1.24 0.52 -1.24 0 0 0 1.15" 1.17 -0.0244' 2-C3H~Ct.H) 2.66 0 2.66 6.27 0 0 0 0 0 0 0 0.86" 0.97 -0.1145' 2-CN -0.57 0 -0.57 2.17 0 0 0 0 1.898 0 0 inact 1.2746 3-CH2 0.56 0.56 0 0 0.52 -1.24 0 0 0 0 0 1.35

47' 11 1.12 0 0 0 0 0 1.15 1.4 0 0 0 1.2348 2,3,5-4) 3 2.00 1.12 2.17 2.3 2.B 0 0 0 0 0 0.00.From reference 35.fi The listed values are the actual values minus the value for

"H" so that the unsubstitutcd compound (14) can have zero value for all the parameters.b C: EDm (mmoljkg). Testcd subcutaneously as water-soluble HCI salts by the hot plate method; d. A. E. Jacobson arM E. L. May, J. Med. Chern. 8,563 (1%5).< Dcrived from eq 12 of reference 35.4 These derivatives were synthesized following the Craig's plot analysis.~ -0.62: E..OCHI + (E..c)~ - E..CH): -0.55 + (-1.31 + 1.24).,

Estimated from BI.ocH)'1 -0.94: E..ocH) + (Ec2H) - E..cH3) :: -0.55 + (-1.63 + 1.24).~ Omitted in deriving eq II of reference 35.,

0.06: 1I').S-(OCH))3 + 1I'OCH) :: 0.08 - 0.02.I Assuming that a hydrogen bond cannot be formed because of unfavorablc conformation forced by the di-ortho-substituents.. The value of 1I').S-(CH)>Jwas used.I Because of the preferred perpendicular conformation of the biphenyl, maximum dimensions were used for the steric effect, i.e., E, (L) and B, werc used instead of E.

(5) and B,.m Assunring the bulky phenyl group prevents "OCr.H9" to be a hydrogen-bond acceptor.

"Activity was observed in 4 to 5 out of 10 mice tcsted.

394 8 Physical Chemistry, Molecular Modeling. QSAR of Arylpiperidine Analgesics

among these three compounds. Common areas of reactivity, potentialenergy minima, and charge densities were identified. However, this workonly reinforces findings from earlier studies and does not provide newinsights.

B. QSAR Studies

Benzoic acid esters of l-methyl-4-piperidinol possess analgesic activity,as revealed by the hot plate assay (33,34). The more potent members ofthis structural class are in the range of morphine and codeine but, ingeneral, display little morphine-like physical dependence liability in mon-keys. Classical QSAR analyses were carried out on the set of compoundsreported in Table 8-5 (35). Among the substituent parameters included inthe study, Lonho (length of ortho substituents) and BI (minimal width ofsubstituents) or E, (Taft steric constant) at the meta and para positionsyield inverse correlations with analgesic potency. Lipophilicity, especiallyin the meta position, and the ability of the meta position to also be ahydrogen bond acceptor are found to enhance analgesic potency.

Cheng et al. (35) developed individual QSARs for ortho, meta, para,ortho andlor meta, meta, andlor para sets of substituents, and for theentire data base. In SOme cases (for example, the meta-substitutedderivatives), the number of terms in the QSAR is large compared to thenumber in the data set. This leads to concern regarding the statisticalsignificance and reliability of the QSAR and corresponding conclusions.

The QSAR derived for all the active compounds in the data base is:

log (I/C) = (0.14 ;j: 0.03) E,.pam +

(0.40 ;j: 0.10) HBme'a -(0.72 ;j: 0.18) BI.me" +(0.25 ;j: 0.07) HBpam.;"d -

(0.07 ;j: 0.02) Lonho +(0.51 ;j: 0.17) Pime" + 1.44 (I)

n = 44; r = 0.77; s = 0.166; f = 9.14where C is the EDso (millimoles per kilogram) for average hot plateactivity. HB is the indicator variable for hydrogen-bonding effects, and Piis the measure of lipophilicity. The number of compounds is representedby n, r is the correlation coefficient, s is the standard deviation of fit, andfis the measure of statistical significance.

Equation (I) is not a particularly good fit to the biological data. The2,4,6-trimethyl, 2,6-dimethoxy, and 2-phenyl derivatives were poorlypredicted, with rather large residuals. The authors offer no reasons why

"z

.t.'"o..=«

o~=0':::~

§o,

N<<;;0

o .<I~

00o~~

oI

cz N

0<;:)0~ .0<I~

~<~o~ .0<I~

:;;~o,

NNNNo

0:~o,

< ~;!; ~;!;~;;; ~;;; ;;; ~;;;~~~~~~~0

0 0 0 0 0 III Molecular Modeling and OSAR Studies 397"

, , , , , ,1f.~U

~00i'1 ~~~thesecompounds are outlyers or what changes or additions might be made0 < N N N N N

-1!,

'E ~~~~~~toequation 1 in order to improve the fit. On the other hand, equation 1 is;s N N N N N N .- II0 0 0 0 0 0 0 ~f.;: , , , , , ,

definitive in showing what factors should improve or decrease analgesic"

OJu "if potency, that is, the QSAR can be tested.z~° ~~°

..ii: ~~~~:!: u"; A QSAR analysis of 13 compounds involving 3-methylfentanyl and its'" '" '" ~C:=;s ".00 0 0 0 0 0 "" analogs was performed using quantum mechanical indices calculated usingo 0, , , , , , .~ t::0_

the CNDO/2 molecular orbital method as potential activity correlates""'"

c ~0(36). The compounds, EDso values, and some of the quantum mechanical~~§

~.-~8.eo OJ

:Ii 00 :g ~~:Eindices are reported in Table 8-6. It was found that the following quantum~~~"E

Q~'-' 00~~~~..

'" '".. ~.. < "ii chemical indices correlate with the activity: (a) the 1T-electron density on

~~~"E the {3substituent of the I-ethyl group arising from the molecular orbital0_ ~. 00 ~~. ~-. ..E":': closest to the HOMO and locating on this substituent (Dw); (b) the. ::EN ;!. ~§~,

~:!-g,~~:>+': ~~~~B electron density of piperidyl nitrogen atom arising from MOs locating~...J- o!::- 0 0 o!::- 0 o~ . u

"0

° . , .\ dominantly on it (DN); (c) the energy level of the unoccupied 1T orbital,::E~~~:>

which may be the LUMO or the orbital nearest the LUMO and locates on...J 0_ ~. N. 00. g:'f :8'f ~. .8 '0'0 ::E- ~~. 00 , 00 , E ~the {3 substituent of the I-ethyl group (Ew). Because the variation of the:> + ~~~~:':" M'" ~~~" ~o.

. ~--:~ --:~'"

II .U ...J- o!::- o!::- o!::- o!::- o!::- o!::- o 1= ~substituent in the I-position of the piperidyl ring has only a small effect on> -5 -6~"...J

'0 ct.:: the phenylpropanamide linked to the 4-position, it was not possible to~01).. C1f

° 00. 0. ~. N. :£'f ". .5tii ~evaluatethe effect of amide oxygen and nitrogen on the activity.". 0 ::E ~~,"

, ~,5i

c.":: '1:;1i

'" :> ~~~~~"M" ~" ~-e"E The activity of the compounds and the related quantum chemical indices~. ~--:~ . ~EO"...Jo!::- o!::- o!::- o!::- o!::- ce:- o ,

"0

are shown in Table 8-7. The results of several regression analyses are" -5 ;;.5c0'0 0

" "'- "u _

~< N< ~< o". ° 3. §- ,,-~~~- ::E ~o °

, ~o . 0. 0- , _0 ~..!. .It '€"0 0 ~0 ~~~o. ~. Table 8.7cict 6< 6..{ .z 6,5 ~f~c . :r ° - 0"~~'- ';S ';S , , - ';S ~0.>. o ~Activityand Quantum Chemical Indices of Some~0..;;.C° .D .. c

Compounds""b~.5 ~.§.C ::E

~° ° 1;:< ~< -< ,,< ~< ]~'O>. :r::E

;:; ::10 ::10 ",A ~- ::10 Compound_0 :;::E g I;;tii-S '0 a' ~~~~~No. Log(1/ED,,) D. DN E.0 :r- 6.< 6..{ 6";' 6< 1~ o..j, 0;;"=::; u

"0.0

';S ';S ';S ';S ';S o""> i:I:.- 0M

" ~~1= 1 1.7570 0.2705 0.3761 0.1311- ...J0 ~(;j II II 2 1.5703 0.3769 0.5404 0.1292.

" g f f0 " ~< N< N< 3 1.1433 0.2697 0.5905 0.t2310 0 a_ I;:- ~8_ :;a:E~'6 go"'"

::EN NO ~o. ;;;0 N ~o. 4 0.9970 0.2216 0.9464 0.1396.5 d!- ~~~~.':f-Q.0<- 6.{ ~z

0" 0 "":z 1: ci~.. :r 0_° - 5 0.8881 0.6291 0.7623 0.1385';s I~ ,

';S, , o 0~0

E go~ 7 0.7029 0.7631 0.9633 0.1469E 0-'0~"S: 8 0.1523 1.3222 0.6842 0.1645.c~U S;;~~ N

"~° N ~'0;;. 0 9 0.1343 1.17323 § i:> M ~e:g §E Q ~~M 8 ~~~~" 10 -0.0380 0.8579. "'- 0 0

~'"] c:.>-;::

C - 0.1~N ,c"a. 11 -0.1967 1.4197 1.2577 0.1616.:2~~ 12 -1.2308 1.5472 1.5653 0.17600

0 . z 013 -1.3783 1.5874 0.6903 0.1421E I I I I I § ~-S

0 N N g..B B'" N N

I :c N :c a From reference 36."0C :c :c U :c U e :;;13c 0 U U N I

UI b The serial number of the compound refers to Table 8.6..~ I I I "0,,~:c

" ~c;~M'"

U :c :c :c :c~:c :c N

I u-u N D-U For the meaning of symbols see text..0 :c :c1:: E~~;;:;: 0 D-U U

6U

6:z

Cn~:c:c

Ie}~1> D-U ~~Mf:'" o 0

L~~II1~..

LJ ~";ij::;c-oO 0

E E U '0.'". 0 e ~g;;;

j:;;

'0 0 Li. «1).-;::~0; ~~"'... z

~" = ~~"-o 0

Significance Test

Regression Equation Correlation Standard CriticalY=a+ beX, + b2X2 Coefficient Deviation F Value T, T,

Log(I/ED,,) = 2.1817 0.9361 0.4342 24.86 F~.)~ = 9.55 5.161 0.948 ["- 1.6027D. - 0.47000N

Log(I/ED,,) = 2.4332 0.9761 0.2346 60.59 F~X)J= 10.9 4.223 3.844- 0.95680. - 1.2477DN'

Log(I/ED,,) = 6.1810 0.7242 0.8515 3.86 Fg_t~=3.26 0.430 1.321- 0.5637DN - 36.2678£.

Log(I/ED,,,) = 5.9953 0.9690 0.2669 46.10 Fi.~ = 10.9 2.600 3.521-1.0827DN" - 30.4102£.

a From reference 36.b Compound 13 has been rejected.


Table 8.8

Correlation between Activity and Quantum Chemical Indices of Some Compounds (Bivariate LinearRegression)

shown in Table 8-8. Table 8-8 shows that for the compounds investigated,three quantum chemical indices listed correlate with the activity toa certain extent, among which the correlation between Dn and the activityis most significant. The authors suggest, on the basis of the QSAR analysis,that the {3substituent functions riot only as a hydrophobic group, but alsoas an electron acceptor to form an acceptor-donor complex with thereceptor through a charge transfer process.

References

1. A. F. Casy, Med. Res. Rev. 2, 167 (1982).2. P. S. Portoghese, Ace. Chern. Res. 11,21 (1978).3. H. van Koningsvcld, Reel. Trav. Chim. Pays-Bas 89, 375 (1970); J. V. Tillack, R. C.

Seccombe, C. H. L. Kennard, and P. W. T. Oh, Reel. Trav. Chirn. Pays-Bas 93, 164(1974).

4. F. R. Ahmed, W. H. Barnes, and G. Kartha, Chem. Ind. (London) p. 485 (1959); G.Kartha, F. R. Ahmed, and W. H. Barnes, Acta Crystal/ogr. 13, 525 (1960).

5. F. R. Ahmed, W. H. Barnes, and L. A. Masironi, Chem. Ind. (London) p. 97 (1962);F. R. Ahmed, W. H. Barnes, and L. D. Masironi, Acta Crystal/ogr.16,237 (1963); F. R.Ahmed and W. H. Barnes, Acta Crystal/ogr. 16, 1249 (1963).

6. P. S. Portoghese and E. Shetter, J. Med. Chern. 19, 55 (1976).7. D. S. Fries, R. P. Dodge, H. Hope, and P. S. Portoghese, J. Med. Chern. 25, 9 (1982).8. M. Cygler and F. R. Ahmed, Acta Crystal/ogr., Sect. B B40, 436 (1984).9. W. H. De Camp and F. R. Ahmed, Chern. Cornrnun. p. 1102 (1971).

10. K. Hayakawa and M. N. G. James, Can. J. Chern. 51, 1535 (1973).

References 399

11. P. S. Portoghese, Z. S. D. Gomas, D. L. Larson, and E. Shefter,J. Med. Chern. 16,199(1973).

12. A. F. Casy, J. Med. Chern. II, 188 (1968).13. E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, "Conformational

Analysis." Am. Chern. Soc., Washington, D. C, 1981.14. A. F. Casy, Tetrahedron 22, 2711 (1966).15. M. A. Iorio, G. Damia, and A. F. Casy, J. Med. Chern. J6, 592 (1973).16. K. H. Bell and P. S. Portoghese, J. Med. Chern. 16, 203 (1973).17. A. F. Casy and K. M. J. McErlane, J. Chern. Soc., Perkin 1 p. 726 (1972).18. A. F. Casy, F. O. Ogungbamila, and C. Rostron, J. Chern. Soc., Perkin 1 p. 749 (1982).19. A. F. Casy and K. M. J. McErJane, J. Chern. Soc., Perkin I p. 334 (1972).20. A. F. Casy, J. E. Coates, and C. Rostron, 1. Pharrn. Pharrnaco/. 28, 106 (1976).21. A. F. Casy and J. E. Coates, Org. Magn. Reson. 6,441 (1974).22. A. J. Jones, A. F. Casy, and K. M. J. McErlane, Can. J. Chern. 51, 1782 (1973).23. A. J. Jones, C. P. Beeman, A. F. Casy, and K. M. J. McErlane, Can. J. Chern. 5t, 1790

(1973).24. K. H. Bell and P. S. Portoghese, J. Med. Chern. ]6, 589 (1973).25. A. F. Casy, Pmg. O'"g Res. 22, 149 (1978).26. M. Froimowitz, J. Med. Chern. 25, 1127 (1982).27. N. L. Allinger and Y. H. Yuh, Quantum Chern. Progr. Exch. 13, 395 (1980).28. M. M. Abdel-Monem, D. L. Larson, H. J. Kupterberg, and P. S. Portoghese, J. Med.

Chern. IS, 494 (1972).29. M. Froimowitz and P. Kollman, J. Cornput. Chern. 5, 507 (1984).30. G. H. Loew and J. R. Jester, J. Med. Chern. 18, 1051 (1975).31. K. S. A. Razzak and K. A. Hamid, J. Pharrn. Sci. 69, 796 (1980).32. T. L. Breon, H. Peterson, Jr., and A. N. Paruta, 1. Pharm. Sci. 67, 73 (1978).33. J. A. Waters, 1. Med. Chern. 20, 1496 (1977).34. J. A. Waters, J. Med. Chern. 2], 628 (1978).35. c.- Y. Cheng, E. Brochmann-Hanssen, and J. A. Waters, 1. Med. Chern. 25, 145 (1982).36. C Changying and L. Lemin, Int. J. Quanturn Chern. 23, 1597 (1983).

(/

9.Open-Chain Analgesics

I. Methadone and Related Compounds . .A. Modification of the Alkylamine ChainB. Modification of the Ketone Chain . . .

C. Modification of the Diphcnyl Fragment.11. Other Open-Chain Compounds .....

A. Thiamoutene and Related Compounds.R. Benzimidazok-Based Compounds. .C. Cyclohcxylamine-Bascd Compounds.D. Bezy!amine-Based Compounds . . . .E. Miscellaneous Open-Chain Compounds

References

40040641\425135436436438441444445

1. Methadone and Related Compounds

Methadone (I), the first of the open-chain analgesics, was discovered atI.G. Farbenindustrie at Hoechst-am-Main in Germany during World WarII in the course of work on spasmolytic compounds (1,2).

'\r' 0 ~ 0

'"I

'"I

2

Its narcotic-type analgesic activity was unexpected, since it lacked anyobvious resemblance to previously known compounds. Despite the factthat there was a morphine shortage at the time of its discovery, methadonewas not used as an analgesic until after the war. Its analgesic potency isabout twice that of morphine, and it was apparently tested at excessivedoses, leading to adverse side effects (2).

Much of the early literature uses the name amidon or amidone. Thisname was soon abandoned in favor of methadone in order to avoidconfusion with other products (2).

Methadone exhibits all of the usual narcotic-type activities: analgesia,sedation, respiratory depression, constipation, physical dependence, anta-gonism by nalorphine and related compounds. It is distinguished by itsgood oral activity and long duration of action. Despite its general similarity

400

Methadone and Related Compounds 401

~CN

\~

+ YNMe'i

CI

NaNH2 EtMgBr-~

I" +

, 2Scheme 9-1. Synthesis of methadone and isomethadone (reference 6).

to morphine, a number of differences have been observed. Physicaldependence and withdrawal symptoms are reported to be slower in onsetand less intense with methadone than with other narcotic analgesics (3).Methadone exhibits less depressant activity than morphine (2) and pro-duces less euphoria (4). It also has a local anesthetic effect (5) and isreported to be weakly antihistaminic (2). Interestingly, all efforts toproduce open-chain narcotic antagonists have been unsuccessful.

Methadone is commonly used orally in outpatient maintenance therapyfor narcotic-dependent individuals (3) because it has relatively good oralactivity and a long duration of action. Its lower level of euphoria andsedation, slow development of tolerance, and slow development of with-drawal symptoms make it particularly suitable for such use.

The original synthesis of methadone (6), shown in Scheme 9-1, led to amixture of four diastereomers, dl-I (methadone) and dl-2 (isometha-done), in approximately equal amounts. Schultz et al. (7) explained theapparent rearrangement on the basis of the postulated aziridinium in-termediate 3, which could be opened by attack at either of the ring carbonatoms. The synthesis reported by Bockmuhl and Ehrhart (1), Scheme 9-2,also led to a mixture of methadone and isomethadone.

3

Easton and co-workers (8) reported a synthesis of methadone in whichisomethadone was not produced. As shown in Scheme 9-3, diphenylaceto-nitrile was condensed with propylene oxide to form a furanone-imine. Thiswas opened with phosphorus tribromide to form the alkyl bromide, which

402

g;' CN

'" +""I~

9 Open-Chain- Analgesics

hB,. 8,..

Be

+

EtMgSr

~

+

2Scheme 9-2. Synthesis of methadone and isomethadone (reference 1).

f},y

I CN

I""+

~

~o

1Scheme 9-3. Methadone synthesis of Easton and co-workers (reference 8).

was subsequently reacted with dimethylamine to form the usual nitrileprecursor. Yields in the final step were reported to be less than 10% forboth the bromide and the chloride.

Another ~ethadone synthesis in which isomethadone contaminationwas avoided was reported by Morrison and Rinderknecht (9). In thisapproach (Scheme 9-4), diphenylacetonitrile was condensed with chloro-acetaldehyde diethyl acetal. The deprotected aldehyde was converted tothe methyl carbinol with methyl Grignard, and then to the chloride. As inthe Easton synthesis, the reaction of the chloride with dimethylamineproduced a very low yield.


g;CN

'" +""I~

CI'"'y0E'DE'

1) NaNH2

~2) H+,H20 CHO

1) MeMg I

~21 SOC/2

c

Scheme 9-4. Methadone synthesis of Morrison and Rinderknecht (reference 9).

f}1 CN'" +

""I~

EtMgBr-2

Scheme 9-5. Isomethadone synthesis (reference /0).

Isomethadone, which is somewhat less active as an analgesic thanmethadone, was also synthesized by methods that preclude contaminationwith methadone. In one case (10), the postulated aziridinium intermediatewas avoided by formylating the amine,as shown in Scheme 9-5. The formylprotecting group was subsequently reduced to a methyl group, and thenitrile was converted to the ketone in the usual way with ethyl Grignard.Alternatively, these authors took advantage of the fact that the secondarytosylate is more reactive than the primary chloride (Scheme 9-6) inselectively preparing the primary chloride. In contrast to the methadonesyntheses described above, this compound reacted with dimethyl amine in58% yield.

Both methadone and isomethadone contain an asymmetric center. Asmight be expected, the stereoisomers have different levels of analgesicactivity. Thorp and co-workers (11) resolved the nitrile precursor andprepared (+)- and (- )-methadone. Larsen el al. (12) subsequently re-solved (+)- and (- )-methadone using d-tartaric acid. Thorp (13) found thelevorotatory (- )-isomer to be about twice as active as morphine by

4049 Open-ChaIn Analgesics

;}I CN

'" + '-("CI~ OTs

I",

NHMez

+

EtMgBr-2

Scheme 9.6. Isomethadone synthesis (reference 10).

subcutaneous administration in rats, and he reported the dextrorotatory(+ )-isomer to be inactive. Other workers (14) found analgesic activity inthe (+ )-isomer, although the (- )-isomer was reported to be 7-50 times aspotent. At least two laboratories (13,14) reported studies in which theracemic mixture was more toxic than either isomer alone. For instance,Scott ef al. determined LD50 values of 21,29, and 31 mg/kg in mice for the(:t)-, (-)-, and (+)-isomers, respectively. Furthermore, they observedthat the (- )-isomer produced death in mice over a relatively long period oftime (up to 8 hours), while the (+ )-isomer resulted in death very rapidly ornot at all, suggesting that toxicity may Occur by different mechanisms forthe two isomers. This may account for the apparent synergistic toxicityobserved for the (:t) mixture.

Differences in activity between the (+)- and (- )-isomers could, inprinciple, be due to differences in dish-ibution, metabolism, and/or excre-tion between the two isomers. However, Sung and Way (15) showed thatthe two isomers have very similar tissue distribution. Furthermore, theyshowed that the two isomers have almost identical rates of metabolism andpH optima for metabolism in liver slices. Sullivan and co-workers alsofound little or no difference between the two isomers when comparingmetabolic patterns and excretion. The differential analgesic activity be-tween the isomers was ascribed to differences in receptor binding for thestereo isomers (16). This suggestion was substantiated when receptorbinding assays became available. The more active (- )-isomer of metha-done exhibited receptor affinities of 4 x 10-9 to 2 x 10-8 M, while the(+ )-isomer had values of 1 x 10-7 to 3 X 10-7 M (17-19).

Isomethadone also exhibits different levels of analgesia in the twostereoisomers. The levorotatory (- )-isomer was shown to be the moreactive form, being about 40 times as active as the (+ )-isomer on sub-cutaneous administration in mice (20,21).

Methadone and Related Compounds405

o-a'.I li A I H.. I

--- "- HO'-""" NHCH,HO~C NH-CHO __SOCIZ

~

CI~ ,CHONI

CH,

diphenyl_

ace ton i t r i Ie) HCOOH

---4

EtMgBr

(-1-,

Scheme 9.7. Synthesis of (- )-methadone from D-( - )-alanine (reference 23).

The absolute stereochemistry of the more active (- )-methadone wasshown to be R in 1955 by Beckett and Casy (22). They converted both thenitrile precursor of (- )-methadone and D-(- )-alanine to the dextrorota-tory amine 4. Beckett and Harper (23) later carried out the synthesis of(- )-methadone using D-(- )-alanine as a starting material, as shown inScheme 9-7. The analgetically more potent (- )-isomethadone was shownby Beckett ef al. (24) to have the S absolute configuration by relating it to(- )-a-methyl-i3-alanine.

4

At least eight metabolites of methadone have been detected in humans.The major metabolic pathway is apparently N-demethylation, although theN-demethylated compound is not isolated as such. It is reportedly anunstable compound that rapidly cyclizes (25). Accordingly, the firstmetabolite identified was the cyclic compound 5 (26). Sullivan andco-workers later identified several other cyclic N-demethyl and N,N-bis-demethyl compounds, to which they assigned the structures 6 (27), 7 (28),8 (28), and 9 (25). In addition, they isolated the carboxylic acid 10 (28), thephenyl ring-hydroxylated compound 11 (25), and the a1cohol12 (25). Ofthese, only compound 12 exhibited analgesic activity of its own. Sullivanand Due (25) indicated that the methadone N-oxide that Beckett ef al.isolated from urine (29) is a storage artifact rather than a metabolite.

406

'"

~5

OH OH

9 Open-Chain Analgesics

.

7 . 9

HO

10 11 12

The structure-activity relationships derived by modification of themethadone structure will be considered in four sections. The first will dealwith changes, in the alkylamine chain, the second with changes in theketone fragment, and the third with the diaryl portion of the molecule. Thefourth will cover phosphorus and sulfur analogs of methadone.

A. Modification of the Alkylamine Chain /Removal of the amine nitrogen completely abolishes analgesic activity

(2). Quatemization of the amine decreases activity substantially. Thequatemized methadone analog 13 and the isomethadone analog 14 re-portedly showed about 1I80th of the activity of methadone ';:hen adminis-tered subcutaneously to mice.

13

Numerous variations of the dimethylamino group have been tried.Bockmuhl and Ehrhart (1) found the highest activity in methadone analogshaving pyrrolidine, piperidine, or morpholine substitutents (Table 9-1).

Methadone and Related Compounds407

Table 9.1

Structure-Activity Relationships inMethadone Analogs withVariation of the Amino Groupo

c

R Activityb

-NMe2 (methadone).Pyrrolidyl.Piperidyl-Morpholinyl

5-105-10

710

Q Data from reference 1.b Relative to meperidine = 1.

Dupre el al. (30) carried out a more extensive exploration of theN-substituents in the nor~ethadone series (Table 9-2). Among the N,N-diaikyl compounds, the dimethyl compound (normethadone, IS) had thehighest activity. As the alkyl groups increased in size, analgesic activitydecreased rapidly; the di-n-propyl and di-n-butyl compounds showed littleor no activity, and the benzyl and dibenzyl derivatives were completelyinactive. In compounds having cyclic amines, the pyrrolidine, piperidine,and morpholine derivatives all showed higher analgesic activity than thedimethyl compound, with the best activity in the morpholine derivative.Methyl substituents on the piperidine or morpho line ring decreasedactivity substantially, except in the case of 4-methyJpiperidine. Com-pounds 16-19, having 7- or 8-membered ring amine substituents, showedlittle or no analgesic activity (31).

1517

19 19

408

Table 9-2


Structure-Activity Relationships inNormcthadone Analogs with Variationof the Amine Substituents a

R Activityb

-NMe,(15)-NEI2-N(nPr),-N(nSu),-N(Me)ben,yl-N(benzyl),Pyrrolidine

Piperidine

Morpholine

2-Methylpiperidine

3-Methylpiperidine

4-Methylpiperidine

2,6-Dirnethylpiperidinc

3-MethylmorphoJine

3,5-Dimethylmorpholine

J0.7-10-0.30-0.3oo42-37o0-0.330-0.31.51.5

" Data from reference 30.b Relative to meperidine = 1.

/

~Changes in the alkyl chain connecting the amine to the diaryl ketonehave also been explored. The analgesic activities of (-)- and (+)_methadone (1) and of (-)- and (+ )-isomet.hadone (2) were describedpreviously. In both pairs, the levorotatory-( - i-isomer was substantiallymore active than the dextrorotatory isomer (13,/4,20,21). In the case ofmethadone, the more active isomer has the R absolute configuration (22),while the more active isomethadone isomer has the S configuration (24).Normethadone (15) was found to be substantially less active than either(:t)-methadone or (:t)-isomethadone (32), as shown in Table 9-3. Bock-muhl and Ehrhart (1) report that replacing the a-methyl group inmethadone with an a-ethyl substituent (20) produced an inactive com-pound. Lengthening the alkyl chain by one or two atoms, as in compounds21-24, also produced compounds with little or no analgesic activity(1,30,32).


Table 9-3

Relative Analgesic Activities ofMethadone Isomers,Isomethadone Isomers,and Normethadone"

Compound EDs~/

(ot)-Methadone (I) 1.6(- )-Methadone 0.8(+ )-Methadone 26(ot)-Isomethadone (2) 2.5(- }-Isomethadone 1.2(+ )-Isomethadone 50Normethadone (IS) 16.6

a Data from reference 32.bED50 in milligrams per kilo-

gram, subcutaneous administra-

tion in mice. Under these condi-tions, morphine had an ED50 of

3.t. mg(kg.

zo21 22

"N 0\ /

23

Henkel et al. (33) investigated the stereoisomers of 5-methylmethadone(25). Attempts to utilize the Easton synthesis (Scheme 9-3, reference 8)with cis- and trans-2-butene-oxide were unsuccessful in this system, leading

25

"

n-bu.tyl

n i tf i te

12' CH2N2

410

o..",<.fh>,ta...,:~..o 9H

R~../ \..,H NHMe2 ~-f-R

R~CH) + CH'-f-HNMe,

(.is' Or- +"'hS-~-",<+e/le-o""<ie. .dlphenyl_acetonitri le/

.0,CCN JC,CH)-f-HCH,-cr-H

NMe',

1 J BULi

---72) TsCI

~ C-CONH,

"CH -C-H,I

CH-C-H, ,NMe,

0,C-CO.R,CH-C-H, ,CHT~-H

NMe,


1

diphenyl_

acetonitrile

base

~,C-Co,R,H-f-CH)

CH-C-H, ,N"',

1Etli

Scheme 9-8. Synthesis of erYlhro- and threo-5-methylmethadone (reference 33).l..:t I-threo

either to an olefin or a despropionyl compound. The synthesis employed bythese workers, shown in Scheme 9-8, introduced the troublesome dimethyl-amino group at an early stage by opening cis- or trans-2-butene-oxide withdimethylamine. The resulting alcohol was then converted to the tosylate.In the case of the threo isomer, the tosylate readily formed an aziridiniumintermediate that could be reacted in situ with diphenylacetic ester anion toform the ester shown, which was readily transformed to the desired ketonewith ethyllithium. The erythro tosylate proved to be much less reactive,necessitating a modification of the synthesis. In this case, the tosylate wasreacted with diphenylacetonitrile anion to form the nitrile, which wasconverted to the ketone in four steps. The threo racemate contains the

\

I Methadone and Related Compounds 411

c

5S,6R stereoisomer, which combines the absolute configurations of themost active isomers of both methadone and isomethadone. Interestingly,this racemate showed no agonist or antagonist activity, indicating that thechiral centers do not behave independently. In contrast, the erythroracemate was more than five times as potent as methadone on sub-cutaneous administration.

B. Modification of the Ketone Chain

The ketone functionality of methadone is relatively unreactive, failing toform a semicarbazone or to reduce with aluminum isopropoxide, sodiumamalgam, or Raney nickel/hydrogen (34). Isomethadone is even moreresistant to catalytic hydrogenation (35). Nevertheless, one of the firstmodifications made to the methadone structure was reduction of theketone to an alcohol.

I. Methadols and Acylmethadols Reduction of the ketone in metha-done can, in principle, give rise to two pairs of diastereomers. Hydrogena-tion of racemic methadone over platinum oxide catalyst gave rise to asingle dl pair (34). Lithium aluminum hydride reduction of methadoneproduced the same dl pair (35), which was named a-methadol (36).Pohland and co-workers (37) showed that hydrogenation of (+)_methadone produced (- )-a-methadol, and (- )-methadone produced (+)-a-methadol. May and Mosettig (38) later showed that the {3-isomers werethe major product in the sodium/isopropanol reduction of methadone;lesser amounts of the a-isomer were formed but could be removed byfractional crystallization. In the case of the {3-methadols, the sign ofrotation is the same as that of the parent ketone (38). Reduction to thecarbinol substantially decreased the analgesic activity in both the a and {3pairs, but it was found that analgesic potency could be restored byacetylating the alcohols (20,38). Table 9-4 lists analgesic activity data forracemic and resolved methadone, a- and {3-methadols, and a- and {3-acetylmethadols (20). It can be seen that the {3-methadols are generallymore active than the a-methadols and that the acetyl derivatives are moreactive than the parent ketones. It is interesting to note that the most activemethadols (a-I and (3-d) are derived from the least active ketone (d-methadone) .

Isomethadone (2) fails to react with hydrogen-platinum oxide (35,36);however, it can be reduced with lithium aluminum hydride to produce asingle dl pair, which is referred to as a-isomethadol (39). As was found formethadone, the (3-isomer was the major product of the sodium-isopropa-nol reduction of the ketone (39). In the isomethadone series, (+)-isomethadone is reduced to ( + )-a-isomethadol and to (- )-{3-isomethadol.

412 9 Open-Chain Analgesics

Table 9-4

Analgesic Activities of Methadone, Methadol,

and Acetylmethadol Stereoisomers'"

Compound ED",b EDsoc

(::!:)-Methadone 1.6 9.2C(- )-Methadone 0.8 8.0

(+ )-Methadone 25.7 89.3

a-('"

)-Methadol 18.9 10.9a-( + )-MethadoI 24.7 61.8a-( - )-MethadoI 3.5 3.8

/3-('"

)-MethadoI 7.3 67.3/3-(- )-Methadol 7.6 36.7/3-( + )-Methadol 63.7 70.0

a-(::!: )-Acetylmethadol 1.2 4.0a-( + )-Acetylmethadol 0.3 1.6a-( - )-Acetylmethadol 1.8 1.1

(3-(:!: )-Acetylmethadol 0.8 2.6/3-( - )-AcetylmethadoI 0.4 2.0/3-( + )-AcetylmethadoI 4.1 5.1

Compound ED50l> EDsoc

(:!: )-Isomethadone 2.5 23.0(- )-Isomethadone 1.2 24.4( + ).Isomethadone 49.8 d

a-(:!: )-IsomethadoJ 66.8 d

a-( + Hsomethadol 60.7 d

a-( - ).Isomethadol 91.7 13213-(

'")-Isomethadol 12.3 30.3

/3-(- )-Isome'hadoI 58.7 93.9/3-(+ )-Isome'hadoI 6.2 40.7a-(:!: )-Acetylisomethadol 4.8 11.2a-( + )-Acetylisomethadol 2.7 10.4a-( - )-Acetylisomethadol 62.7 104(3-(::!:)-Acetylisomethadol 17.4 55.4/3-(- )-Acetylisomethadol 10.9 35.013-(+ )-Acetylisomethadol 70.6 164

R R' ED5Qb

H Me 16.9H H 0.98Ac Me(U) 1.09Ac H(27) 0.48

Table 9-5

Analgesic Activities of Isomethadone,Isomethadol, and Acetylisomethadol Stereoisomers'"

Morphine 2.3 3.7

"Data from reference 200 ~b ED5Q in milligrams per kilogram for sub.

cutaneous administration in mice.C

EDso'in milligrams per kilogram for oraladministration in mice.

" Data from reference 20.b

EDso i~ milligrams per kilogram for subcutaneous

administration in mice.C

EDso in milligrams per kilogram for oral adminis.tration in mice.

d Inactive at nonlethal doses.

Table 9.6

Analgesic Activities of Some

Secondary Amine and Tertiary

Amine Derivatives of a-Methadol"

However, acetylation reverses the sign of rotation for both the a- andi3-isomers. Leimbach and Eddy (20) measured analgesic activity sub-cutaneously and orally in mice for racemic and resolved isomethadone, a-and i3-isomethadols, and a- and i3-acetylisomethadols, as shown in Table9-5. i3-Isomethadol was found to be less active than isomethadone, anda-isomethadol was almost completely inactive. Acetylation of theisomethadols restored much of the anagesic activity, and on oral adminis-tration some of the acetates had better activity than the parent ketone, butnone of these compounds was as active as the corresponding methadonededvatives.

The methadols and acetylmethadols are among the few compounds inwhich secondary amines show good analgesic activity (40a). In fact, for theexamples shown in Table 9-6, the secondary amines are more active thanthe corresponding tertiary amines. a-Acetylmethadol (26) has been used

" Data from reference 40b.b

EDso in milligrams per kilogramon subcutaneous administration inmice.

414

Table 9-'


Receptor Binding of Stereoisomers ofMethadone, a-Methadol, a-Acetylmcthadol, andSome N-Demethylated Compoundsa

Compound

(+ )-Methadooe(- )-Methadonea.( - ).Methadola.( + ).Methadol

a-( - )-N-Normethadola-( + )-N-Normcthadola-( - )-N,N-Dinormethadola-( + )-Acetylmethadola-( - )-Acetylmethadola-( + )-N-Noracetylmethadola-( - )-N-Noracetylmethadola-( - )-N,N-Dinoracetylmethadol

IC", eM) Lh 1'\ I1.3 X 10-7 1305.0 x 1O~9 5.05.1 x 10-' S 102.0 X 10-7 ~O8.0 X 10-10 O.g6.3 x 10-' ~301.5 x 10-' ISO4.3 X 10-9 "(..33.5 x 10-' 353.6 x 10-' :n.1.0 x 10-' 1.01.6 x to-9 I,b

a Data from reference 19.

clinically as an analgesic (40a) and in maintenance therapy for narcotic-dependent persons (41). Its properties are generally similar to those ofmethadone, with better oral activity and a longer duration of action. Themajor route of metabolism for this compound is N-demethylation to theN-nor and N,N-dinor compounds 27 and 28 (42). Nickander et al. (43)have showed that in humans 27 and 28 reach plasma levels at which thesemetabolites may be responsible for part of the analgesic activity and muchof the long duration of action. The dinor compound 28 has an EDso aboutequal to that of the parent compound (43).

26 27 28

Horng and co-workers (19) measured receptor binding for thestereoisomers of methadone, a-methadol, a-acetylmethadol, and some ofthe N-demethylated compounds. Their results are shown in Table 9-7. Thereceptor affinities measured are in good accord with the measured analge-sic activities (cf. Table 9-4). The N-demethylated compounds that showedgood analgesic activity (Table 9-6) also have relatively high receptoraffinities.


Table 9-8

Ester Analogs of Methadonea

c

RActivity

(meperidine = 1)Activity

(ED""mgjkg)R'

.Me

.Et-iPf.Et.Et

-NMe2-NMe2-NMe2-morpholinyl-piperidyl

9.91861

<0.10.2

a Data from references J and 38.

2. Esters Replacement of the ketone side chain by an ester is readilyaccomplished from the nitrile precursor, either by sulfuric acid hydrolysisand esterification (1) or by heating with the alcohol, sulfuric acid, andammonium chloride in a scaled tube (30). Table 9-8 lists analgesic activitiesfor a number of ester analogs of methadone. As the ester was varied frommethyl to ethyl to isopropyl, activity decreased in this series. Eddy et al.(38) found that the ethyl ester analogs of methadone (29) and isometha-done (30) have essentially the same analgesic activity. Compound 29 hadan EDso of 18 mg/kg and 30 had an EDso of 19 mg/kg. A further summaryof structure-activity relationships in the esters is found in Table 9.9 forcompounds in the normethadone series. Here, too, the methyl ester wasmost active, with activity decreasing as the ester group became larger.

29 30

3. Ketones Bockmuhl and Ehrhart (1) explored variations of theketone side chain, as shown in Table 9-10. The highest activity was foundin the ethyl ketones. The aldehyde, methyl ketone, n-propyl ketone, andisopropyl ketone showed substantially less analgesic activity. The allyl andisobutyl ketones again showed reasonable analgesia, but phenyl andbenzyl ketones were very weak analgesics.

416

Table 9-9 Table 9-10

Ketone Modifications"Ester Analogsof Normethadone"

o

9 Open-Chain'Analgesics

ActivitybR R'R Activityb

-H-H-Me-Me-Et-Et-nPc-nPc-iPe-allyl-iBu-phenyl-phenyl-benzyl

-Me-Et.iPe-nBu-phenyl-benzyl

20.5I

<0.2<0.2

0.5

" Data from refer-ence 1.

bSubcutaneously,

relative to meper-idine = 1.

-piperidyl-NMcz-morpholinyl-NMez-morpholinyl-NMez-morpholioyl

-NMcz-piperidyl-piperidyl-piperidyl-morpholioyl

-NMcz-morpholinyl

3o

0.5-0.750.5531

0.25-0.50.25

2-32

<0.2<0.5

o

a Data from references J and 2.b

Subcutaneously, relative to meper-

idine = 1.

4. Amides Only a few simple ami des were reported by Bockmuhl andEhrhart (1), and these showed little or no analgesic activity. For instance,the primary amide 31 was completely inactive, and compound 32 was muchless active than meperidine. Janssen and Jageneau (44) have reported anextensive study of amide analogs of normethadone, methadone, andisomethadone; their results are summarized in Tables 9-11, 9-12, and 9-13.

Amide analogs of normethadone are shown in Table 9-11. Most of thesecompounds had very weak analgesic activity. Primary and secondaryamides were completely inactive, and the best activily was seen when thedimethylamide or pyrrolidine amide was employed. None of these com-pounds approached the activity of methadone.

Table 9-12 lists several amide analogs of methadone. Unlike theketones, this series exhibited no significant increase on addition of themethyl substituent exto the amine nitrogen. The most active analgesic inthis series was an N,N-dimethylamide, which was still much less active thanmethadone.

c

III

Methadone and Related Compounds

Table 9-11

Amide Analogs of Normethadone"

417

R ED", (mgfkg)R'

-NH,-NHMe-NMez-NMe2-pyrrolidyl

-pyrrolidyl

-piperidyl-piperidyl-morpholinyl

-morpholinyl

Methadone

-piperidyl-piperidyl-piperidyl-morpholinyl

-piperidyl-morpholinyl



Inactive>100>100

22.370.013.6

>10073.0

>10095.0

5.2

" Data from references 1 and 44.

Table 9-]2

Amide Analogs of Methadone"

,

R

-NHMe

-NHEt-NMe2-pyrrolidyl-pyrrolidyl-pyrrolidyl

-NEt2Methadone

R'

-morpholinyl-morpholinyl-morpholinyl

-NMe2-pyrrolidyl-piperidyl-piperidyl

ED", (mgfkg)

53.962.024.5

>100> 50> 50> 25

5.2

" Data from reference 44.

Q Q" ;,O-p-o O~p-ou0u'" N----., dYNMe.Ib

~Ib.. 3. 36

4]8

Table 9.13

Amide Analogs of lsomethadoneu


R

-NIIMe-NIIMe-NilE'-NIIEt-NIIEt-NHiPr-NHnBu-NlltBu-NH-benzyl

-NMe2-NMe2-NMe;!-NIIMeEt-NEt;!-NEt2-pyrrolidyl

~-pyrrolidyl

-pyrrolidyl

-pyrrolidyl

-pyrrolidyl

-pyrrolidyl

-pyrrolidyl

-piperidyl

-morpholinyl

Methadone

R'

-NMc;!-morpholinyl

-NMe;!-piperidyl-morpholinyl

-morpholinyl

-morpholinyl

-morpholinyl

-morpholinyl

-NMe2-piperidyl

-morpholinyl

-morpholinyl

-piperidyl

-morpholinyl

-NMe2-pyrrolidyl

-piperidyl

-piperidyl (+ )-isomcr

-morphoJinyl

-morpholinyl (+ )-isomer

-morpholinyl (- )-isomcr

-morpholinyl

-morpholinyl

ED", (mg/kg)

]46

44.114554.025.982.0

>100>100>100

21.011.41.38

26.0>50

32.116.320.913.27.801.250.645

>15059.070.05.2

U Data from reference 44.

31 3233

Janssen and Jageneau found Ihe highest analgesic activities in amideanalogs of isomethadone, as shown in Table 9-13. Among Ihe monoalkylamide analogs, the elhyl amide showed the best analgesic potency(26 mg/kg); smaller or larger alkyl groups decreased activity. In Ihe dialkyl

I

I Methadone and Related Compounds419

(oic1x.base

)

C I-CH2-CH2-NR2

Scheme 9.9. Synthesis of phosphorus analogs of methadone (reference 46). n= 1, 2;X = -phenyl, -ethyl, -ethoxy.

c amide series, the order of potency observed was dimethyl> methylethyl >diethyl. The pyrrolidine amide series exhibited the best analgesic activities,with one compound showing greater analgesic activity than melhadone.The dextrorolatory isomer of this compound is called dextromoramide, 33.This compound had an ED50 of 0.645 mg/kg, in sharp contrast to thelevorotatory isomer, which had an ED50 > 150 mg/kg. Changing thepyrrolidine amide tOlhe piperidine amide decreased the analgesic potencyby a factor of about 40. In clinical sludies (45), dextromoramide was found10 be aboul twice as potenl as morphine. Occurrence of side effects such asrespiratory depression, sedation, and nausea were about equal for dextro-moramide and morphine. Dextromoramide-induced analgesia had a shor-ter duration of action than morphine-induced analgesia.

5. Phosphorus and Sulfur Analogs Shelver and co-workers (46) pre-pared a series of monoaryl and diaryl phosphorus analogs of melhadone.These compounds were prepared as shown in Scheme 9-9, by reacting Iheanion of the arylphosphorus starting material with the appropriate chloro-alkylamine. The yield in the alkylation reaction was found 10 be highlydependent on the solvent and conditions. The analgesic activities measuredfor the monoaryl series are shown in Table 9-14. None of these com-pounds approached Ihe level of activity shown by morphine. The diphenyl-phosphine oxides were found to be substantially more active than thediethyl phosphonates and the single dielhylphosphine oxide tested. Surpris-ingly, Ihe most active compound found in this series was 34, a diethylamine. This compound was still only about one-fifth as active as morphine.In the only instance where a methyl substituent was tried on the alkylaminechain, Ihe isomethadone analog 35 was about four limes as aclive as thedesmelhyl compound.

The diaryl phosphorus analogs prepared by Ihese workers are listed inTable 9-15. In this series, no dielhylphosphine oxides and only one

Table 9-14

Monoarylphosphorus Analogs of Methadone"

0 0I ' ,R

A ",P' RCHIR'

R R'

-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-OEt-OEt-OEt-OEt-EtMorphine

-CHrCH2-NMe2-CH2-CHrNEt2-CHrCHrpyrrolidyl-CH2-CHrpiperidyl

-CH2-CHrmorpholinyl-CH(CII,J-CH,-NMe, (35)

-CHrCHrNMe2-CHrCHrNEt2-CHrCHrpiperidyl

-CHrCH2-morpholinyl-CHrCHrpiperidyl

85.16.2

47.924.710.119.7

248.7144.2105.0104.4191

1.3


ED50' milligrams per kilogram, subcutaneouslyin mice.

Table 9-15

Diaryl Phosphorus Analogs of Methadone"

R R'

-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-phenyl-OEtMorphine

-CHrCH2-NMe2-CHrCHrNEt2-CH2-CHrPyrrolidyl-CHrClI2-piperidyl

-CH2-CHrmorpholinyl-CH(CH,)-CH,-NMe,

-CH2-CHrCH2-NMe2-CH,-CH,-p;peridyl (36)

10.215.213.311.217.214.622.111.11.3


EDso. milligrams per kilogram. subcutaneouslyin mice.

II

I

r

I

II

I

r

r


grl:::: -..::::

CI

I", grl:::: ~SH

I",

RX

+ gr"'l

SR

I""'"

I

thio re.~

Db.se

SOa.R

Scheme 9-10. Synthesis of sulfone analogs of methadone (reference 47).

diethylphosphonate were prepared. The latter compound, 36, was themost active diaryl derivative tested, but was still only one-eighth as potentas morphine. Among the diphenylphosphine oxides, variations in thealkylamine side chain seemed to make very little difference. Even theinsertion of an extra methylene group in the alkylamine chain caused onlya small decrease in analgesic activity.

Klenk et al. (47) prepared a series of methadone analogs in which theketone side chain was replaced by an alkylsulfone or arylsulfone. Scheme9-10 outlines the general synthetic approach to these compounds. Ben-zohydryl chloride was first converted to the mercaptan by treatment withthiourea. The mercaptan was treated with the appropriate alkyl or arylhalide and then oxidized to the sulfone with hydrogen peroxide. Finally,treatment with base and a chloroalkylamine produced the target com-pounds. The structure-activity relationships observed by these workers aresummarized in Table 9-16. In general, the alkyl substituent on the sulfonehad to be methyl or ethyl in order to obtain good analgesic activity; propyland p-toluyl sulfones were much less active. The most active compoundswere those having a methyl substituent a to the amine nitrogen (as inmethadone), although this point was not explored extensively.

Tullar and co-workers (48) later resolved the stereoisomers of one of thesui fones, compound 37, by making the d-bitartrate salts. The levorotatoryform was found to be about 20 times more active as an analgesic than thedextrorotatory form.

37

6. Imines Cheney et al. (49) prepared a series of imine and acyliminederivatives of methadone-type ketones. These imines were readily pre-pared from the nitrile precursor and were found to be quite stable,

412 9 Open-Chain' Analgesics

Table 9-16

Analgesic Activities of Sulfone Analogs of Methadone"

gx: SO,R

'"I

R'

"-['I

R R' Activityb

-Me-Me-Et-Et-Et-Et-Et-nPr-p-loluyl-p-loluyl

-CHrCHrpiperidyl-CH(CH,)-CH,-NMe,

-CHz-CHrNMc2-CHz-CHz-piperidyl

-CH2-CHz-NEtz-CH,-CH(CH,)-NMe,-CH,-CH(CII,)-piperidyl-CH,-CII(CH,)-NMe,-CH,-CII(CH,)-NMe,-CHrCHz-piperidyl

++++

++++++

++++++

+oo

a Data from reference 47.h

+++ = approximately equal to methadone;

+ + = approximately equal to meperidine;

+ = approximately equal to aminopyrine.

presumably due to steric hindrance. Acylimines were prepared by treatingthe imines with acetyl or propionyl chloride. Many of these compounds,listed in Table 9-17, showed analgesic activity equivalent to that ofmethadone; none was found to be more potent. Overall, the acyl deriva-tives showed somewhat less analgesic potency than the parent imines. Thepropionyl derivatives were only slightly less active than the acetyl analogs.

Eddy and co-workers (38) also examined the analgesic activities of aseries of imine derivatives (Table 9-18). Compound 38, the imine ofisomethadone, showed about one-fifth the analgesic potency of morphine.The most active imine dierivative examined by these workers was 39,which was equal to or slightly better than morphine in potency. Theacetylimine derivatives of isomethadone and methadone (40 and 41,respectively) were both much less active than morphine in this study.

3' 39

Table 9-17

Methadone and Related Compounds

Imine and Acyliminc Analogs of Methadone"

423

R Analgesic DoschR'

-H-H-H-H-acctyl-acetyl-propionyl-prepianyl

-acetyl-acetylMethadone

-CHrCHz- morpholinyl-CHrCHz-piperidyl-CII(CII,)-C!!,-NMe,

-CII,-CH(CH,)-NMe,

-CII,.CH(CH,)-NMe,

-CII(CH,)-CH,-NMe,

-CHrCllr morpholinyl-CII,-CH(CH,)-NMe,

-CHrCHrpiperidyl

-CHz-CHz-pyrrolidyl

1512.51512.512.530t2.5255075t2.5

'"Data from reference 49.

b Subcutaneous analgesic dose (milligrams per kilogram)

in guinea pigs.

Table 9.18

Imine and Acetylimine Derivatives of Methadone'"

R R'

-H-H-acetyl-acetylMorphine

-CH(CH,)-CII,-NMe, (38)-CH(CII,)-ClI,-morpholinyl (39)-CII(CII,)-CH,-NMe, (40)-CH,-CH(CH,)-NMe, (4!)

151-36040

3.t

" Data from reference 38.b ED5o, milligrams per kilogram. subcutaneously in mice.

424

40

9 Open-Chain Analgesics Methadone and Related Compounds

41 48

7. Other Modifications of the Ketone Replacement of the ketone sidechain by the methyl or ethyl ether (50) produces the active isomethadoneanalogs 42 and 43. These were reported to be two and five times as potent,respectively, as meperidine. These compounds also exhibited local anes-thetic activity.

42 43 54

Variable results were seen in acyloxy analogs. The acetoxy- and prop-ionyloxynormethadone analogs 44 and 45 were very weak as analgesics(2). The acetoxyisomethadone analog 46 exhibited moderate activity (32).The (+ )-isomer of the propionyloxyisomethadone analog 47 was quiteactive, while the (- )-isomer of this compound showed no analgesic activity(51).

49

52

57

46

59

55

425

50

o53

56

o58

60

reduction products, the alcohols 54 and 55 (2). Esterification of thealcohols (compounds 56-58) did not significantly alter the pharmacologicalresults (2). Weak analgesic effects were observed for the olefin 59 and thechloride 60 (32,34).

47

. Most other modifications of the ketone have produced very weak ormactIve compounds. Complete removal of the ketone side chain ofmethadone (compound 48) resulted in total loss of analgesic activity (34).The mtnle precursors of methadone and isomethadone (compounds 49 andS0,. r~spectively) were ~lso devoid of analgesic effects (32). No analgesicactIvIty was observed m the carboxylic acid derivatives 51-53 or their

C. Modification of the Diphenyl Fragment

Most modifications of the phenyl groups have resulted in substantial lossof analgesic activity. However, replacement of the diphenyl-carbon frag-ment with N-arylpropionamide derivatives has produced a number ofhighly active compounds. These results will be examined in the followingtwo sections.

426

Table 9-19

9 Open-Chai~ Analgesics

Phenyl Group Modifications in Normethadone Analogs"

:.;(X

R ActivitY'R' x

-phenyl-phenyl-phenyl-phenyl-phenyl-p-Cl-phenyl

-allyl-benzyl-cinnamyl-m-OMe-phenyl-m-OH-phenyl-p-Cl-phenyl

-piperidyl-piperidyl-NElz-morpholinyl

-morpholinyl

-NMcz

ooo

<0.2<0.2o

a Data from reference 1.b Activity relative to meperidine = 1.0.

Table 9-20

Phenyl Group Modifications in

Ester Analogs of Normethadone"

R R' Activityb

-phenyl -c-hexyl <0.2-c-hexyl -c-hexyl <0.2

-ftuorenyl- 0-phenyl -ethyl 0-ethyl -ethyl 0-phenyl -benzyl 0

Q

Data from reference J.b Activity, relative to meperi-

dine = 1.0

1. . Modification of the Phenyl Groups In their extensive paper de-scnbmg structure-activity relationships in methadone analogs. Bockmuhland Ehrhart (1) described several analogs in which one or both phenylgroups were modIfied. As may be seen in Tables 9-19 and 9-20, few ofthese analogs retained any analgesic activity. ]n the ketone series (Table9-19), meta-hydroxy and meta-methoxy substitution produced weakly

.


o

O'YNM<,

benzyl MgCI)

propionic

anhydr I de

61

Scheme 9.11. Synthesis of propoxyphene and related compounds (reference 52).

active compounds, while the para-chI oro compound was inactive. Replace-ment of a phenyl ring with allyl, benzyl, and cinnamyl also producedinactive compounds. Among the esters (Table 9-20), saturation of one orboth phenyl rings produced weak analgesics. Tying the two phenyl ringstogether into a fluorenyl derivative destroyed analgesic activity, as didreplacement of one or both phenyl rings with ethyl groups. Replacing aphenyl ring with a benzyl group also resulted in an inactive compound.

When the ketone side chain was replaced by a propionyloxy group and abenzyl group was substituted for one of the phenyls, a number ofcompounds with moderate analgesic activity were discovered (52). In-cluded in this series was propoxyphene, compound 61, which has founduse in the treatment of mild to moderate pain in humans (53). Thesecompounds were prepared as shown in Scheme 9-11 (52). The appropriatebenzophenone was treated with benzyl magnesium chloride to form mainlyone diastereomer (called a) of the carbinol. Acylation with propionic oracetic anhydride produced analgesics with about 1/lOth the potency ofmethadone. The {3diastereomer was without analgesic activity.

Pohland and Sullivan resolved the a carbinol with camphorsulfonic acidand prepared the a-( +)- and a-( - )-isomers of propoxyphene (51). Theanalgesic activity was found to reside only in the (+ )-isomer. Pohland et al.

61

(54) later succeeded in resolving the amino-ketone precursor to thecarbinol using dibenzoyl tartaric acid, providing an alternative stereoselec-tive synthesis.

The absolute configuration of a-( +)-propoxyphene was established bySullivan et al. (55) via chemical transformation to products of known

R R' ADso.n

.H 1 .H 8

.H 1 -m-Me 2

.H 1 -p-Me 3

.H 1 .p.Cl 6

.H 1 -p.F 6

.H 2 -H 4-H 2 -m-Me 14-H 2 -p.NH2 16-OCH, 2 -H 15-H 3 17Compound 65 4Meperidine 11Morphine 3

4289 Open.Chafn Analgesics Methadone and Related Compounds 429

o

TO an i line

)

propionic

li A IH..

propionic

anhydrideanhydride

63

Scheme 9-13. Synthesis of phenampromid (reference 57).

62

Scheme 9-12. Synthesis of diampromid (reference 57).(e.g., compound 64) produced by treating the intermediate diamines withalkyl chloroformates (58); however, the analgesic activities seen in thecarbanilate series were quite low.

Structure-activity relationships for a number of propionanilides relatedto diampromid are outlined in Table 9-21 (59). Only one substitution wastried on the N-phenyl ring; a meta-methoxy substituent reduced analgesic

configuration. They showed that the analgetically active diastereomer had2S,3R absolute configuration. Shortly thereafter, Casy and Myers (56)confirmed the 3R absolute configuration and pointed out that this is thesame configuration as in the active (- )-isomethadone.

Racemic propoxyphene was included among the analgesics for whichPert and Snyder (17) measured receptor binding. Consistent with itsrelatively low level of analgesic activity, this racemate showed a bindingconstant of 1 x 10-6 M.

2. N-Aryl-Propionamides In 1959, Wright and co-workers (57) re-ported a series of N-phenylpropionamide derivatives having good analgesicactivity. The most interesting compounds in this series were the methadoneanalog diampromid, 62, and the isomethadone analog phenampromid, 63.

Table 9-21

Propionyl AnilidesQ

62 63

Diampromid was reported to have analgesic activity between that ofmorphine and meperidine (57). Phenampromid was somewhat less active,being about equal to meperidine in rats (57) and equal to codeine in mice(58). Diampromid was prepared from 2-bromopropionanilide, as shownin Scheme 9-12 (57). The resulting amide was reduced with lithiumaluminum hydride to the diamine, then acylated with propionic anhydride.In the synthesis of phenampromid (Scheme 9-13), the 2-bromopropionylamide of piperidine was first reacted with aniline (57). Reduction withlithium aluminum hydride and acylation were again employed to producethe desired product. These workers also explored a series of carbanilates

a Data from reference 59.b

ADso = subcutaneous dose (in milligramsper kilogram) that elevates the rat tail radiant

heat response time by 100% in 50% of theanimals.

Compound ADsOh

(00)-63 13(-)-63 9(+)-63 36Morphine 3


Table 9.22

Analgesic Activities of Stereoisomers of PhenampromidQ

QData from reference 58.

hAD~ = subcutaneous dose (in milligrams per kilo-

gram) that elevates the rat tail radiant heat response timeby 100% in 50% of the animals.

activity by a factor of 4 relative to the unsubstituted compound. In thebenzylamine series (n = 1), substitution on the benzyl aromatic ringenhanced the potency somewhat. When the amine substituent was changedfrom benzyl to phenethyl (n = 2), however, ring substitution decreasedanalgesic activity significantly. Analgesic activity was also reduced whenthe amine substituent was lengthened to phenylpropyl (n = 3), but com-pound 65, with an N-cinnamyl substituent, showed good activity.

Wright and co-workers (58) resolved the stereoisomers of phenampro-mid, 63, using malic acid. As may be seen in Table 9-22, the (- )-isomerwas about four times as active as the (+ )-isomer. Portoghese (60) showedthat (-)-63 has the same absolute configuration (R) as the more potentstereoisomer of isomethadone (20), indicating that these compounds havethe same stereochemical requirements.

The stereoisomers of diampromid, 62, and the N-benzyl analog 66 wereprepared (61) as outlined in Scheme 9-14. Resolution was carried out on anN-benzyl diamine, with tartaric acid as the resolving agent. The (-)_diamine was acylated with propionic anhydride to form (- )-66. The benzylgroup was removed by catalytic hydrogenation, and the phenethyl sidechain was added in the last step to yield (+ )-diampromid. Analgeticpotencies measured for these compounds are shown in Table 9-23. Notethat the more potent isomers, (- )-66 and (+ )-62, are derived from thesame precursor and therefore have the same absolute configuration.Portoghese and Larson (63) related the more active isomers to L-(+)_


[jre50lved with

tar tar ic: aC id)

phenylacetaldehyde)

Scheme 9-14. Synthesis of enantiomers of (-)-66 and (+)-diampromid (reference 61).

I-t-)-diarnpromid

Table 9.23

Influence of Alkyl ChainLength on Stereosclectivityin Enantiomeric Propionanilides a

n Compound

2

(00)-66R-(+)-665-(-)-66

(00)-625-(+)-62R-(-)-62

(00)-675-(+)-67R-(-)-67

8Inactive4.33.73.6

11.712.58.9

11.9

3

" Data from references 61 and62.

bAD50 = subcutaneousdose (in

milligrams per kilogram) that ele-vates the rat tail radiant heat re-sponse time by 100% in 50% of

the animals.

0,) 0,)

aNiO orNiO6' 69

0,) 0,)aNio NNiO

70 71

R EDsoh R., EDsobR, R, R,.H Inactive

-H -H .H Inactive-Me 100 (in mice) -H

-E' (68) 9.3 68 -Me .H -H -H 9.3-Et -H -H -H >20

-nPr 20-Me -H -H 50

-c-hexyl Inactive -Me

-phenyl 35 .Me -H -Me -H 5-6-H -H -Me -H Inactive

a Data from reference 65. -H -H -Me .Me Inactive

b ED50. milligrams per kilo- a Data from reference 65.gram. subcutaneously in rats b ED50, milligrams per kilogram, subcuta-(except as indicated).

neously in rats.


alanine, indicating that they have the S absolute configuration. This is insurpnsmg contrast to the finding that the more active isomer of methadonehas the R absolute configuration (64). Portoghese and Riley (62) extended

~he~r study of stereochemical effects to the phenylpropyl analog 67. Asmdlcated m Table 9-23, stereoselectivity in the analgesic activity falls off asthe alkyl chain length increases. For compound 67, the difference inactivity between the (+)- and (- )-isomers is not statistically significant.

H,!tmann et al. (65) published an extensive structure-activity study onproplram, .68, and related compounds in which the phenyl ring of theproplOnamhdes was. replaced with a pyridyl ring. These compoundsshowed mixed agomst and antagonist properties. The best analgeticacllVlltes were seen for the 2-pyridyl compounds; the 3-pyridyl isomer 69was somewhat less active, and the 4-pyridyl compound 70 was completelymacllve as an analgesic. Methyl substituents on the 2-pyridyl ring de-cre~sed or abo~ished analgesic activity, but the 4-phenyl compound 71 was15 times as active as 68. The latter compound was not pursued because italso showed relatively high toxicity.

Variation of the acyl group (Table 9-24) indicates that the propionylsubstituent IS clearly superior to other choices. The formamide andcyclohexylcarboxamide are inactive, and the butyryl and benzoyl deriva-lives show only moderate analgesic activity.

Anal~esic activity i~ highly sensitive to substitution on the alkyl chainconnectmg the two mtrogen atoms (Table 9-25). A single methyl substi-tuent on the carbon adjacent to the amide nitrogen (i.e., compound 68)appears to be nearly optimum; compounds having an ethyl group or two


Table 9-24

Variation of the Acyl Groupin the Propiram Series"

Table 9-25

Variations of the Alkylpiperidine Group in thePropiram Series"

[

methyl groups in this position show much less analgesia. When there are nomethyl substituents present or when there are methyl groups on the carbonadjacent to the piperidine, analgesic activity is absent. The exception is themixture of four diastereomers having one methyl group on each carbon;both racemic pairs were as active as propiram.

Nearly 50 variations of the dialkylamino group were reported; somerepresentative examples are listed in Table 9-26. Most of the noncyclicdialkyl amines showed only moderate or weak analgesic activity. A notableexception was compound 72, which was tested as a mixture of twodiastereomeric racemates. Among the simple cyclic amines, the piperidylderivative was most active. Compounds having 7- or 8-membered ringsalso showed good activity, but those with 5- and 9-membered rings weremuch less potent. Substituted piperidines showed a range of activities,from the weakly active 2,2-dimethyl derivative to the relatively potent 3,3-dimethyl derivative. Here again, phenyl substitution produced an ano-malous effect; while a 4-methyl substituent decreased activity by a factor of3, the 4-phenyl derivative was more than 100 times as potent as theunsubstituted parent compound. Numerous bicyclic amines were alsotested; several of these are also included in Table 9-26.

The absolute configurations of the (+)- and (- )-isomers of propiram,68, and the analogs 73, 74, and 75 were reported by Wollweber (66). In all

Compound EDsOb

(=)-68 11 (mouse)5(+)-68 13 (mouse)R(-)-68 18 (mouse)

(=)-73 0.98 (rat)5(+)-73 1.6 (rat)R(-)-73 1.2 (rat)

(=)-74 2.34 (rat)5(+)-74 5.07 (rat)R(-)-74 1.87 (rat)

(=)-75 100 (mouse)5(+)-75 37 (rat)R(-)-75 61 (rat)

434

Table 9.26


Variations of the Dialkylamino Group in the Propiram

Series"

NR,

Dialkyl amines

-NMe2-NEtl-N(nPr),-N(Me)-benzyl-N(Me)-phene'hyl-N(Me)-CH(CH,)-CH,-phenyl (72)

(mixture of 4 diastereomers)

Cyclic amines

-pyrrolidyl

-piperidyl (68)

-azacycloheptyl

-azacyclooctyl

-azacyclononyl

-2-Mc-piperidyl

-3-Me-piperidyl

-4-Me-piperidyl

-4-phenylpiperidyl

-2,2-Mc2-piperidyl

-3,3-Mel"piperidyl

Bicyclic amines

-3-azabicyclo[3.1.0]hexanyl

-3-azabicyclo[3.2.1]octanyl

-2-azabicyclo[ 2.2.2 ]octan y I

-l,2,3,4-tetrahydroisoquinolyl

16018

>20>20

19.51

429.3

12.011.742.65.894.96

260.07

34.70.98

1.581.09

11.0Inactive


EDSIh milligrams per kilogram, subcutaneously inrats.

cases, Ihe difference in analgesic activity between the (+)- and (- )-isomerswas small. Table 9-27 shows that, for propiram and 75, the S-( + )-isomer ismore active, while the R-( - )-isomer is more active for compound 74. The Sconfiguration in this series gives the same arrangement of functional groupsas the R configuration in isomethadone (the order of precedence changesin going from the diphenylmethyl substituent of isomethadone to the

II Other Open-Chain Compounds 435

Table 9-27

Analgesic Activities ofStereoisomers of Propiram andRelated Compounds"

[

a Data from reference 66.b

EDso, milligrams per kilogram,

administered subcutaneously.

o~ I ~~N'V'N~~ N I I

7273

7574

acylaminopyridine of propiram), so the more. active stereoisomer ofpropiram corresponds to the more active stereOIsomer of Isomethadone(20).

II. Other Open-Chain Compounds

There are several groups of open-chain analgesic compounds that cannotbe considered as analogs of the methadone series. These wtll be dtscussedin the following sections.


th i eny I L i)

7.Scheme 9-15. Synthesis of compounds in the thiambutene series (reference 67).

A. Thiambutene and Related Compounds

Adamson (67) described a series of dithienyl-alkenylamines and alkanol-amines having analgesic, spasmolytic, anti histaminic, and local anestheticactivity. Included in this series was thiambutene, 76, which has analgesicpotency comparable to that of morphine. As shown in Scheme 9-15,thiambutene was prepared by treating an aminoester with two equivalentsof thienyllithium to form the tertiary carbinol shown. Yields in thisreaction were satisfactory only in the case of tertiary amines. The carbinolsin this series were without analgesic activity, although they did possessantispasmodic and local anesthetic effects. Treatment with acid producedthe olefin.

76 77

The analgesic activities of these compounds (68,69) are listed in Table9-28. Among the cyclic amine derivatives prepared, the azacycloheptylanalog was most potent. The piperidine and pyrrolidine derivatives alsoshowed good activity, but methyl-substituted piperidines were somewhatless active, and the aza cyclooctyl derivative was quite weak. Beckett andco-workers (69) resolved the optical isomers of thiambutene and foundthat the dextrorotatory isomer was about six times as potent as thelevorotatory isomer. The more active stereoisomer was shown (22) to havethe same absolute configuration as the more potent (- )-isomer of metha-done.

Saturation of the olefinic double bond was tried on several compounds inthis series (70). These compounds were generally one-fourth to one-fifth asactive as the parent olefins. .

B. Benzimidazole-Based Compounds

Hunger el al. (71,72) reported the synthesis of a number of extremelypotent analgesics built upon the benzimidazole ring system. The synthesis

II Other Open-Chain Compounds

Table 9.28

Analgesic Activities ofDithienylbutenylamines Q

[ }rNR'

437

NR,

(;0)- .NMe,(+)- -NMe,(-)- -NMe,

-NMeEt-NEl2

(;0)- -pyrrolidyl(+ )- -pyrrolidyl(-)- -pyrrolidyl

-piperidyl-2-Me-piperidyl-3-Me-piperidyl-4-Me-piperidyl-azacycloheptyl-azacyclooctyl

Activityb

1.071.70.271.71.00.71.5t0.641.1

0.5-0.60.6-0.90.6-0.91.3-1.8

0.05-0.10

a Data from references 68 and 69.b Activity upon subcutaneous

injection in rats. Morphine = 1.

of these compounds was accomplished in two steps, as illustrated in Scheme9-16. The most active compound in their series, 77, was reported to beabout 1000 times as potent as morphine on subcutaneous administration inrats. Some of the structure-activity relationships derived for this series are

.O,NO

NH,

I +.&

NHz

o,NOhCI-CH2-CH2-NEt~

~Q77NEtt OE.t

Scheme 9-16. Preparation of analgesics in the benzimidazole series (reference 71).

Activity

R R' Subcutaneousb Oral"

.H -4-CI 0.1 0.5-NOz -4-CI 1 5-N02 -3,4-(OMe), 10 3-NOz .4-0Me 30 15-N02 -4-0Et WOO 1250

Isomer Activity

A StrongB ModerateC WeakD WeakB ModerateB WeakB ModerateA ModerateB WeakB WeakA ModerateB WeakB ModerateA ModerateB WeakB ModerateD InactiveD Weak

438 9 Open-Chain A"nalgesics

Table 9-29

Analgesic Activities of Some Benzimidazole-BasedCompounds a

Q

Data from reference 72.b Activity on subcutaneous injection in rats.

Morphine = 1.e Activity on oral administration in mice.

Morphine = I.

listed in Table 9-29. Substituents on the benzimidazole and phenyl ringswere shown to have a profound effect on the level of analgesic activity.Comparing the last two compounds in the table, simply changing apara-methoxy group to a para-ethoxy increased analgesic activity by almosttwo orders of magnitude in rats and mice. Eddy (73) reported EDso valuesfor these two compounds of 0.015 and 0.001 mglkg.

78

C. Cyclohexylamine-Based Compounds

Several structurally diverse groups of analgesics have in common theaminocyclohexane or aminocyclohexene fragment. Satzinger (74) reporteda series of cyclohexene derivatives prepared by the Diels-Alder reactionshown in Scheme 9-17. The reaction produced both cis and trans isomers.In some cases, the olefin was subsequently saturated by hydrogenation.Qualitative measures of analgesic activities for these compounds are


Scheme 9-17. Preparation of compounds related to tilidine (reference 74).

[

summarized in Table 9-30. Most of these compounds have only weak ormoderate analgesic activity, but tilidine (78) showed good activity. In aclinical study, (75) a 50-mg dose of tilidine was found to produce analgesiaequivalent to that of a 100-mg dose of meperidine. Dubinsky and co-workers (76) found that in rats, analgesia was correlated with levels of atilidine metabolite in the brain and suggested that the metabolite mightcontribute to the analgesic activity observed.

Table 9-30

Structure-Activity Studies for Tilidine and Related CompoundsQ

HR 'R'

60.

cJ6R' cJ6R'er6R'

. C D

R R'

78 .COOEt

.COOEt

.COOEt

.COOEt

.COOEt

.NEtz

.pipcridyl

.NHMe-pyrrolidyl

.COCH,

.CN

.COOiPr

.COOMe

.CH,OH

.CH,OAcQ

Data from reference 74.

440

6R-benzoyl chloride

9 Open-Chain f\nalgesics

Scheme 9-/8. Preparation of cydohexylmethyl benzamides (reference 77).

Harper el al. (77) reported the preparation of 79 and several relatedbenzamidomethylcyclohexylamine derivatives by the method shown inScheme 9-18. While 79 has a potency close to that of morphine, most of thecompounds reported in this series are substantially lower in analgesicactivity (77,78). Table 9-31 shows the analgesic activities reported forcompounds of this type.

Table 9-31

Analgesic Activity of Some

Cyclohexylmethylbenzamides"

R R'

-H.2-CI-3.CI.4-CI3,4.CI,3,4-CI,3,4.CI,4.F-HMorphineCodeine

-NMe2-NMe2-NMe2-NMe2-NMe2-piperidyl-N' -Me-piperazinyl-NMe2-piperidyl

15.560

9.55.02.5

>!OO>100

5.0>100

2.0t7.0

" Data from references 77 and 78.b EDso, in milligrams per kilogram. on

subcutaneous injection in mice.


[' D, Benzylamine-Based Compounds

Two compounds (82 and 83) with moderate analgesic activity weredescribed by Wilson and Pircio (79). These compounds were prepared bytreating the cyclobutane derivative 84 with either phenyl Grignard orcyclohexyl Grignard reagent. These two compounds were reported to beabout equal to codeine on intraperitoneal administration.

NMe'z

82 83

~Workers at Dai,!ippon in Japan (80,81) prepared an extensive series of

diphenyleihylpiperazine compounds such as 85. Selected results from thiswor-kale shown' in Table 9-32. Among the piperazine substituents ex-amined, medium-sized (6,7,8) cycloalkyl rings gave the best results. Goodactivity was also seen for the para-methoxybenzyl group (compound 86) atthis position; the para-nitrobenzyl derivative was inactive. Substituents onthe two phenyl rings decreased analgesic potency in most cases. The

8.

N)'-N ,

R.

R, R, R, R, EDsob

-H -II -H -H >160-cyclopentyl 36.9-cycIohexyl 3.09-cycloheptyl 5.45-cycIooctyl 3.45-cyclododecyl >160-phenyl >160-iBu > 70-benzyl >160-4-Me-benzyl >160-4-NOz-henzyl >160-4-0Me-henzyl (i:) 15.2

(+) 40.1(-) 13.5

-H -2-Me -H -4-0Me-benzyl 120-3-Me 26.4-4-Me 31.7

-H -H -2-0Me -4-0Me-benzyl 32.5-4-0Me 37.4-2-CI (;0) 79.0

(+) 58.4(-) >160

-3-Cl 48.1-4-Cl 39.7-2-Me 65.2-3-Me 28.0-4-Me 14.1-4-NO, 8.11

-H -4-Me -4-Me -4-0Me-benzyl 98.6-COMe -H -H -4-0Mc-benzyl 80-160-COE! 73.1-COE' -H -2-CI -4-0Me-benzyl >160Codeine 28.1


Table 9-32

Diphenylethylpiperazine AnalgesicsQ

a Data from references 81 and 82.b EDso, in milligrams per kilogram, on subcutaneous injection in mice.

Substituents not listed in the table are assumed to be the same as for thepreceding compound in the table.


8r

p-bromophenyl MgBr)

['

)80Q+ Br

H0>aNM~J

()' 0Br

Scheme 9-19. Synthesis of compounds 80 and 81 (reference 79).

21 phenethy I "'gBr

81

stereo isomers of 86 were resolved, and Ihe dextrorotatory enantiomer wasfound to be about Ihree limes as potent as the levorotatory enanliomer.

Lednicer and Von Voigtlander (82) reported that compound 80 has anED,o in mice of 0.1 /lg/kg, about 10,000 times as potent as morphine.Receptor binding studies by Ihese aulhors showed 80 to have an IC,o of8 x 10-10 M (compared to 2.4 x 10-8 M for morphine). In comparison,the stereoisomer 81 was much less active (EDso of 7-8 mg/kg). Thesynthesis of 80 and 81 is shown in Scheme 9-19. The cyano group of theaminonilrile was displaced by the para-dibromobenzene Grignard reagentto introduce the bromophenyl group.

Yardley and co-workers (83) reported the preparalion of ciramadol, 87.They resolved the compound using tartrate and found the ( + )-isomer to beinactive. The (- )-isomer was shown to have mixed agonist and antagonistactivity, with analgetic activily about two times Ihal of morphine onintraperitoneal, intramuscular, or oral administration. In a clinical study(84), ciramadol was shown to be somewhal more potenl as an analgesic

than pentazocine.

HO~

I",

87 88

Configuration

Isomer A B C ED", "R, R R + >20R, R R 0.9S, S S + >20S, S S >20Meso R S

'">20

Morphine 5.0

" Data from reference 85.b EDso. in milligrams per kilogram, on

intraperitoneal administration in rats.

444 9 Open.Chain Analgesics

Table 9-33

Stereoisomers of Viminol"

E. Miscellaneous Open-Chain Compounds

Vi~inol, 88, is a pyrrole derivative reported (85) to have good analgesicactIVIty and physIcal dependence liability comparable to that of pentazo-cIne.. The compound exhibits both agonist and antagonist activities.VlmInol possesses three asymmetric centers. Della Bella and co-workers(85) separated most of the possible stereoisomers, as shown in Table 9-33.The analgesic potency was found to reside only in the levorotatoryenantiomer of the isomer in which both sec-butyl groups have the Rabsolute configuration. Antagonist activity was found to reside in thelevorotatory enantjomer in which both sec-butyl groups have the Sabsolute configuration.

. Carrano. et al. (86,87) reported the analgesic activity of N-butyroyl-N'-cInnamylplperazIne, 89. ThIs compound was described as having lowphysIcal dependence liability in rodents. It appeared to be particularlyeffective when administered orally.

References 445

References

[

1. M. Bockmuhl and G. Ehrhart, Liebigs Ann. Chern. 561,52 (1948).2. K. K. Chen. Ann. N. Y. Acad. Sci. 51, 83 (1948).3. A. F. Casy. Prog. Dmg Res. 22, 149 (1978).4. H. Isbell, A. Wikler, N. B. Eddy, J. L. Wilson, and C. F. Moran, lAMA, J. Am. Med.

Assoc. 135, 888 (1947).5. F. G. Everett, Anesthesiology 9, 115 (1948).6. E. C. Kleiderer, J. B. Rice, and V. Conquest, Report 981, Office of the Publication

Board, Dept. of Commerce, Washington, D. C. (1945).7. E. M. Schultz, C. M. Robb, and J. M. Sprague, J. Am. Chem. Soc. 69,2454 (1947).8. N. R. Easton, J. H. Gardner, and J. R. Stevens, J. Am. Chem. Soc. 69,2941 (1947).9. A. L. Morrison and H. Rinderknecht, J. Chem. Soc. p. 1478 (1950).

10. M. Sletzinger, E. M. Chamberlin, and M. Tishler, J. Am. Chem. Soc. 74,5619 (1952).11. R. H. Thorp, E. Walton, and P. Ofner, Nature (London) 160, 605 (1947).12. A. A. Larsen, B. F. Tullar, B. Elpern, and J. S. Buck, J. Am. Chem. Soc. 70,4194

(1948).13. R. H. Thorp, Br. J. Pharrnacol. 4, 98 (1949).14. C. C. Scott, E. B. Robbins, and K. K. Chen, J. Pharmacal. Exp. Ther. 93,282 (1948).15. c.-Y. Sung and E. L. Way, J. Pharmacal. Exp. Ther. 109,244 (1953).16. A. H. Beckett and A. F. Casy, J. Pharm. Pharmacal. 6, 986 (1954).17. C. B. Pert and S. H. Snyder, Science 179, 1011 (1973).18. D. T. Wong and J. S. Horng, Life Sci. 13, 1543(1976).19. J. S. Horng, S. E. Smits, and D. T. Wong, Res. Commun. Chem. PathoJ.Pharmacal. 14,

621 (1976). ~ R,UjlTo.. iSl">..4-", A J;p.;.i/lu ,F'II1': i--J...,,{ol,20. D. G. Leimbach and N. B. Eddy. J. Pharmacal. Exp. Ther. 110, 135 (1954).21. E. J. Jenney and C. C. Pfeiffer, Fed. Proc., Fed. Am. Soc. Exp. BioI. 7,231 (1948).22. A. H. Beckett and A. F. Casy, J. Chern. Soc. p. 900 (1955).23. A. H. Beckett and N. J. Harper, J. Chem. Soc. p. 858 (1957).24. A. H. Beckett, G. Kirk, and R. Thomas, J. Chem. Soc. p. 1386 (1962).

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.33. J. G. Henkel, E. P. Berg, and P. S. Portoghese, J. Med. Chem. 19, 1308 (1976).34. E. L. May and E. Mosettig, J. Org. Chern. 13, 459 (1948).35. E. L. May and E. Mosettig, J. Org. Chern. 13, 663 (1948).36. M. E. Speeter, W. M. Byrd, L. C. Cheney, and S. B. Binkley, J. Am. Chern.Soc. 71,57

(1949).37. A. Pohland, F. J. Marshall, and T. P. Carney, J. Am. Chern. Soc. 71, 460 (1949).38. N. B. Eddy, E. L. May, and E. Mosettig,J. Org. Chern.17, 321(1952).39. E. L. May and N. B. Eddy, J. Org. Chern. 17, 1210 (1952).40a. N. A. David, H. J. Semler, and P. R. Burgner, JAMA, J. Am. Med. Assoc. 161,599

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82.83.84.85.

86.

[87.

446 9 Open-Chain A~algesics

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10.Physical Chemistry and Molecular Modeling ofOpen-Chain Analgesics

I. Physical Chemistry Studies of Open-Chain AnalgesicsA. Methadone and homcthadoneB. Methadols and IsomethadolsC. DextromoramideD. Propoxyphcnc . . . . . . .E. Other Open-Chain Analgesics .....

II. Molecular Modeling of Open-Chain AnalgesicsReferences

44R44R451453453454456457

c

I. Physical Chemistry Studies of Open-ChainAnalgesics

The open-chain analgesics exhibit all the activities, side effects, andphysical dependence properties of the cyclic opiates, despite the lack ofobvious structural similarity to the traditional opiates. Numerous physicalstudies have been carried out on these conformationally flexible com-pounds in order to try to find similarities to morphine and arylpiperidineanalgesics.

A. Methadone and Isnmethadone

Beckett (1) proposed that methadone, 1, and isomethadone, 2, arestabilized in a cyclic conformation by intramolecular interactions betweenthe ketone and amino groups. They considered two types of interactions,shown in Fig. 10-1. The hydrogen bond postulated in Fig. IO-Ia shouldstabilize the ionized form, raising the pK" while the lone pair carbonyl-carbon interaction of Fig. IO-Ib should stabilize the un-ionized form and

Fig. 10.1.ence 1).

;:p~ ~~~~ 431 (b)

Possible intramolecular interactions in methadone and isomethadone (refer-

448

Physical Chemistry Studies of Open-Chain Analgesics 449

Fig. 10-2. Proposed solution conformation of methadone (reference I).

lower the pK,. The pK, values measured for methadone and isomethadonewere 8.25 and 8.07, respectively, some 0.1-0.3 pK, units lower than theanalogous compounds lacking the ketone. Beckett proposed the conforma-tion shown in Fig. 10-2 as the receptor active form of methadone.

2

Proton nuclear magnetic resonance (NMR) has been a part of severalinvestigations on methadone conformations. Methadone and isometha-done conformations in chloroform were investigated by Smith (2). Hefound that the two N-methyl groups exhibited nonequivalence, supportinga single preferred conformation. In addition, the C-methyl substituent ofmethadone was shielded by about 0.5 ppm, consistent with acarbonyl-NH hydrogen bonded conformation that places the methylgroup above one of the aromatic rings. The shielding effect was not seen inanalogs having cyano-, hydroxy-, or proton substituents in place of thepropionyl group (3).

Haller and Schneider (4) examined normethadone, 3, and a deuteratedderivative. They calculated proton NMR spectra for the folded (gauche)and extended (antiperiplanar) conformations of the dimethylaminoethylside chain. The experimentally determined spectrum closely resembled thespectrum calculated for the extended conformation.

3

In another study of methadone and isomethadone, Henkel et al. (5)found methadone to be more conformationally mobile than isomethadone,since methadone exhibited a solvent-induced inversion in the circulardichroism spectrum. These authors found that methadone (but not

Compound CDCI.. CD..OD D,O

rhreo.4 6.7 7.0 nd'erythro-4 7.2 7.6 ndthreo-4. DC! "t nd "terylhro-4 . DCt 8.3 6.6 6.0

" From reference 6.b Not determined.

..,

4\0 10 Physical Chemistry and Molecdar Modeling of Open-Chain Analgesics I Physical Chemistry Studies of Open-Chain Analgesics 451

Table 10-1

4

(8.71 and 8.16, respectively), indicative of intramolecular hydrogen bond-ing in the threo compound.

Subsequent X-ray crystallographic studies of these compounds (7,8)showed the erythro compound in a folded conformation and the threo in anextended conformation. The more potent enantiomer of erythro-4 wasfound to have the 55,65 absolute configuration. This finding is consistentwith the result in isomethadone and related compounds; the 5-positionconfiguration is apparently more important than the 6-position configura-tion.

Crystallographic studies have generally confirmed the conformationalflexibility of the open-chain analgesics; no consistent pattern has beenobserved in the structures determined to date. Hanson and Ahmed (9)found methadone hydrobromide to be in an extended conformation. Thecrystal structure of the methadone base, however, showed a foldedconformation (10,11). In this case, there is a close contact between theamine nitrogen atom and the carbonyl carbon (the N-C distance was foundto be 2.9 A, about 0.3 A shorter than the sum of the van der Waals radii ofthe two atoms). This arrangement is essentially the same as that proposedby Beckett (1), shown in Fig. IO-Ia. This attraction induces severaldistortions in the molecule. Several bond angles are distorted fromtetrahedral geometry (109') to 114', and the carbonyl carbon is almost0.1 A out of the plane formed by the atoms attached to it.

In other crystal structure determinations, Shefter (12) found thatisomethadone hydrochloride exists in an extended conformation. Similar-Iy, an extended conformation was observed for the hydrochloride salt ofnormethadone, 3 (13).

Kaufman and co-workers (14) measured pKa values and distributioncoefficients for methadone and a-acetylmethadol. They found that thedistribution coefficients are highly dependent on the temperature at whichthe measurement is made. Since such measurements are routinely made at20 or 25'C and in vivo distribution takes place at 37'C, these authorssuggest that the temperature dependence of the results may have asubstantial impact on the observed distribution behavior.

Vicinal Proton Coupling Constants for threo~ and

erythro-5-Methylmethadooea

isomethadone) underwent rapid proton exchange of the protons a to thecarbonyl group, presumably via an intramolecular amino group participa-tion. They interpreted this to mean that methadone may adopt a foldedconformation, while isomethadone is held relatively rigidly in an extendedconformation.

The erythro and threo isomers of 5-methylmethadone, 4, were preparedand their conformational properties examined by Henkel et al. (6). In thisseries, the threo pair of racemates was without analgesic activity, while theerythro pair was found to be 5.4 times as active as methadone. Table 10-1shows the vicinal proton coupling constants for these compounds and theirsalts in three solvent systems. For the most part, the values observed areconsistent with conformationally flexible molecules, but the very low valueseen for the threo salt was proposed to be due to a strongly hydrogenbond-stabilized folded conformation, as shown in Fig. 10-3. Measurementof pK, values for these compounds gave further support to this suggestion:the threo isomer had a substantially higher pKa than the erythro isomer

Fig. 10-3.encc 6).

,. ,.

l \/ MeC~H

O-trN'=i<HMe

Folded conformation proposed for the analgetically inactive threo-4 (refer-

B. MethadoIs and IsomethadoIsHaving two asymmetric centers, the methadols have presented a more

complex and often contradictory conformational picture. Casy and Hassan(15) carried out an infrared spectroscopic study of a-methadol, {3-methadol, and normethadol (compounds 5 and 6) in nonpolar solvents.They observed evidence of strong intramolecular hydrogen bonds in boththe free bases and salts of these compounds, and proposed the foldedconformations shown in Fig. 10-4.

4\2 10 Physical Chemistry and Molecular Modeling of Open-Chain Analgesics453I Physical Chemistry Studies of Open-Chain Analgesics

~~M'~ H

(a) (b)

Fig. /0-4. Proposed hydrogen-bonded conformations for (a) the free base form and (b)

the salt form of the methadols (reference 15).

Portoghese and Williams (16) also observed strong intramolecularhydrogen bonds in a- and ,B-methadols. They found pKa values of 8.15 and7.85, respectively, for these two compounds and ascribed the difference tothe greater stability of the NH-O hydrogen bond in the a-isomer. Inaddition, it was found that the hydroxyl protons of the methadol free baseswere at unusually low field in the proton NMR spectra (a = 8.6 ppm;,B= 7.9 ppm). These proton resonances had peak widths of 30 and 23 Hz,respectively, consistent with a stronger hydrogen bond in the a-isomer.

In a later paper (17), these authors carried out further studies on themethadols. Here they observed less temperature dependence of the OHresonance in the ,B-isomer than in the a-isomer in the proton NMR spectra;they also reported some concentration dependence of the OH absorptionin the infrared spectrum of the a- but not the ,B-isomer. These results areconsistent with stronger hydrogen bonding in the ,B-isomer.

In their study of the isomethadols (7), Portoghese and Williams (18)again found evidence in the infrared spectra for strong intramolecularhydrogen bonding for the free bases in nonpolar solvents. In this series,the a-isomer appeared to be more strongly hydrogen bonded. Theproton NMR results supported this conclusion; the temperatureeffect on the hydroxy proton was greater in the ,B-isomer than in a. Inaqueous solution, neither appeared to have strong intramolecular associa-tion; the pKa values measured were 7.77 for the a-isomer and 7.76 for the

5

,B-isomer, not much different than those of model compounds incapable ofsuch hydrogen bonding. The absolute configurations of the isomethadolswere determined to be 35,5R for (+ )-a-isomethadol and 3R ,5R for(- )-,B-isomethadol. These authors point out that the analgetically activeisomers of methadol and isomethadol all have a 35 absolute configuration.

Casy and Hassan (19) used optical rotatory dispersion studies todetermine the absolute configurations of the (+)- and (- )-normethadols.They found that the more analgetically active isomer of normethadol hasthe 5 configuration at C-3, just as was found previously for the methadoland isomethadol series.

Shefter (12) reported X-ray crystallographic structure determinations ofa-methadol and a-methadylacetate. The latter compound exhibited anextended conformation, as has been seen in several other open-chainanalgesic structures. However, the alcohol showed a torsion angle betweenthe quaternary carbon and the nitrogen atom of 116', midway between anextended and a folded conformation. In a comparison of six open-chainanalgesic structures, Shefter concluded that there was no clear patternrelating conformation to analgesia in these compounds.

6

.C, Dextromoramide

Dextromoramide is the dextrorotatory (and analgetically more potent)stereoisomer of compound 8 (20). Crabbe et at. (21) inferred from opticalrotatory dispersion spectra that dextromoramide has the same absoluteconfiguration as L-(+ )-5-alanine and, therefore, the same absolute con-figuration as the more active stereoisomer of isomethadone. ..

Bye (22,23) carried out X-ray crystallographic structure determmatlOnsof dextromoramide, both as the bitartrate salt and as the free base. In bothcases, the aminoethyl side chain was found to have an extended ~onforma-tion. Bye compared the X-ray crystal structures of 10 open-cham analge-sics. He reached the same conclusion as did Shefter: there IS no clearconformational preference in the open-chain compounds that can berelated to analgesic activity.

D. Propoxyphene

Three crystal structure determinations have been carried out on propoxy-phene derivatives. Bye (24) used anomalous dispersion effects for chlor-7

NMe, NMeH

. 10

o~

ON1011

4\4 to Physical Chemistry and Molecular Modeling of Open-Chain AnalgesicsPhysical Chemistry Studies of Open-Chain Analgesics

ine to establish the absolute configuration of (+ )-propoxyphene (9)hydrochloride as 2S,3R. This result was consistent with the assignmentmade by Sullivan et al. (9) on the basis of chemical evidence. In thisstructure the aminoethyl side chain is in an extended conformation. Theextended conformation was also found (25) in the crystal structure of thepropoxyphene free base.

N-Norpropoxyphene, 10, is a major metabolite of propoxyphene. Thiscompound, too, exhibited an extended aminoethyl conformation in thesolid state, as determined by Bye (26).

Table 9-2

Analgesic Activity and Conformational Preference for

Propiram and Related Conpounds"

4\\

R EjZ

-CH(CH,)-CH,-piperidyl (II) E-CII,-CH(CH,)-piperidyl Z-CH(CH,)-CH(CH,)-piperidyl (Ihreo) E-CH(CH,)-CH(CH,)-piperidyl (erylhro) E-C(CH,h-CH,-piperidyl E-CH,-C(CH,h-piperidyl Z-CHrCHrpiperidyl Z-CII(CH,)-CH,-3,3-Me,-piperidyl E-CH(CH,)-CH,-3-azabicyclo[3.2.0]hepryl E

9.7Inactive6.45.050InactiveInactive0.982.34

" From reference 28.b

ED50. subcutaneous, in rats.

(UV) maximum at about 260 nm and a methylene chemical shift of 1.7-1.9ppm in the proton NMR spectrum. The Z conformation sh~wed two UVmaxima, one at 267 nm and another at 225-229 nm, and m the protonNMR spectrum the methylene adjacent to the ketone had a ~h~mical shiftof 2.1-2.2 ppm. As can be seen in Table 10-2, compounds eXlstmg ~n the Econformation showed good analgesic activity, while compounds eXlStmg mthe Z conformation were found to be inactive. The predominance of the Econformation also correlates with the presence of methyl substituent(s) onthe carbon adjacent to the amide nitrogen.

Beckett and co-workers (29) measured the pKa values of thiambutene,12, and several related compounds. The presence of sulfur lowered themeasured pKa to 7.5-9.0, compared to 9.3 for the diphenyl analog. Theseworkers postulate an intra molecularly associated conformation, as shownin Fig. 10-6. Such an arrangement would stabilize the neutral form and,therefore, lower the pK,.

In the I ,2-diphenylethylamine series, compound 13 has been reported tobe 0.3-0.5 times as potent as morphine in producing analgesia (30). AnNMR analysis of the proton couplings indicated that the phenykclipsedconformation exists to an extent of about 22%. OptIcal rotatory dispersIOn

.'-

~~Fig. 10-6. Proposed conformation of thiambutene (reference 29).

E. Other Open-Chain Analgesics

The dissociation constants (pK, values) were determined by Wollweber(27) for propiram, 11, and several of its analogs. Propiram had a measuredpKa of 8.92, and the analogs had values ranging from 8.9 to 9.2. Noapparent relationship could be seen between pKa and analgesic activity inthis series.

Geiger and Wollweber (28) used ultraviolet and NMR spectroscopy tostudy the conformations of propiram and related compounds listed inTable 10-2. The pyridine ring was found to be perpendicular to the car-bonyl group, existing in two possible conformations, as shown in Fig. 10-5.In the E conformation the methylene group of the ketone is over thepyridine ring, while in the Z conformation the carbonyl oxygen occupiesthis position. The E conformation was identified by a single ultraviolet

Fig. 10-5. Conformation of propiram and related compounds (reference 28).

456 10 Physical Chemistry and Molccalar Modeling of Open-Chain Analgesics

studies were used to propose that the analgetically active (- )-isomer hasthe R absolute configuration.

~NM"

c12 13

II. Molecular Modeling of Open Chain Analgesics

Quantum chemical calculations have been carried out on methadone, I,to test the hypothesis that it structurally mimics the fused-ring structureof morphine (31). Conformational energies were computed using the(PClLO) method (32) for the nonprotonated and protonated forms.The minimum energy conformation of the protonated form of methadone

exhibits intramolecular hydrogen bonding. However, neither the non pro-tonated nor the protonated minimum energy conformations exhibits muchsimilarity to morphine. This can be seen in Fig. 10-7, which contains the

'.Fig. 10.7. Minimum-energy conformer of methadone superimposed on that of morphine

(reference 31).

References 457

minimum-energy conformer of protonated methadone with its nitrogenatom superimposed on that of morphine (dotted outline).

A conformational study of methadone and some of its analogs wascarried out using molecular mechanics energy calculations (33). The resultsof the calculations are consistent with experimental findings in the follow-ing respects:

1. Isomethadone was found to be less flexible than methadone due tothe proximity of the S-methyl group to the phenyl rings.

2. Methadone has a greater propensity to form an intramolecularhydrogen bond than does isomethadone.

3. The SS ,6R-S-methylmethadone isomer (4) can adopt unusualeclipsed conformations due to the methyl groups on C-S and C-6.

The N-methyl groups of methadone and isomethadone have markedlydifferent conformational preferences. These conformational differencesare postulated to result in each molecule interacting differently with theopiate receptor, which, in turn, may be responsible for the different modesof interaction observed for compounds in this class.

References

1. A. H. Beckett, J. Pharm. Pharmacol. 8, 848 (1956).2. L. L. Smith, J. Pha.rn. Sci. 55, t01 (1966).3. A. F. Casy. J. Chern. Soc. B p. 1157 (1966).4. R. Haller and H. J. Schneider, Arch. Pharm. (Weinheim, Ger.) 306, 450 (1973).5. J. G. Henkel, K. H. Bell, and P. S. Portoghese, J. Med. Chern. 17, 124 (1974).6. J. G. Henkel, E. P. Berg, and P. S. Portoghese, J. Med. Chern. 19, 1308 (1976).7. P. S. Portoghese, J. H. Poupaert, D. L. Larson, W. C. Groutas, G. D. Meitzner, D. C.

Swenson, G. D. Smith, and W. L. Duax, J. Med. Chern. 25, 684 (1982).8. W. L. Duax, G. D. Smith, 1. F. Griffin, and P. S. Portoghese, Science 220, 417 (1983).9. A. W. Hanson and F. R. Ahmed, Acta Crystallogr. 11,724 (1958).

10. H. B. Burgi, J. D. Dunitl, and E. Shefter, Nature (London) New BioI. 244, 186 (1973).tl. E. Bye, Acta Chern. Scand., Sa. B 828, 5 (1974).12. E. Shelter. J. Med. Chern. 17, t037 (1974).13. E. Bye, Acta Chem. Scand., Ser. B 830, 323 (1976).14. J. J. Kaufman, N. M. Semo, and W. S. Koski, J. Med. Chem. 18,647 (1975).15. A. F. Casy and M. M. A. Hassan, Can. J. Chem. 47, 1587 (1969).16. P. S. Portoghese and D. A. Williams, J. Pharm. Sci. 55, 990 (1966).17. P. S. portoghese and D. A. Williams, J. Med. Chem. 12, 839 (1969).18. P. S. Portoghese and D. A. Williams, J. Med. Chem. 13, 626 (1970).19. A. F. Casy and M. M. A. Hassan, J. Med. Chern. 11, 601 (1968).20. P. A. J. Janssen and A. H. Jageneau, J. Pharrn. Pharmacol. 9, 381 (1957).21. P. Crabbe, P. Demoen, and P. Janssen, Bull. Soc. Chim. Fr. p. 2855 (1965).22. E. Bye, Acta Chem. Scand., Ser. B 829, 22 (1974).

458 10 Physical Chemistry and Molecular Modeling of Open-Chain A~algesics

23. E. Bye, Acta Chern. Scand., Ser. B 830, 95 (1976).23a. H. R. Sullivan, J. R. Beck, and A. Pohland, J. Org. Chern. 28,2381 (1963).24. E. Bye, Acta Chern. Scand. 27, 3403 (1973).25. E. Bye, Acta Chern. Scand., Ser. B 829, 556 (1975).26. E. Bye, Acta Chern. Scand., Ser. B 831, 157 (1977).27. H. Wollweber, Eur. J. Med. Chern. 17, 125 (1982).28. W. Geiger and H. Wollweber, Eur. J. Med. Chern. 17,207 (1982).29. A. H. Beckett, A. F. Casy, N. J. Harper, and P. M. Phillips, J. Pharrn. Pharrnacal.8,

860 (1956).30. T. Sasaki, K. Kanematsu, Y. Tsuzuki, and K. Tanaka, J. Med. Chern. 9, 847 (1966).31. G. H. Loew, D. S. Berkowitz, and R. C. Newth, J. Med. Chern. 19, 863 (1976).32. S. Diner, J. P. Malrieu, F. Jordan, and M. Gilliert. Theor. Chirn. Acta 15, 100(1969).33. M. Froimowitz, J. Med. Chern. 25, 689 (1982).

11.

Enkephalins

111.

I. Introduction.. ..II. Opioid Peptide Precursors.

A. ProopiomelanocortinB. Proenkephalin .C. Prodynorphin .Peptide Synthesis ......A. Amino Acid Protecting Groups . .B. Methods of Amide Bond Synthesis . .. .. ...Enkephalin Selectivit~es for the 1-1.and S Opiate ReceptorsMinimum Enkephalin Chain Length Necessary for Analgesia.Structure-Activity Relationships in the EnkephalinsA. The Enkephalin N-Terminus.. .B. Tyrosinel Structure-Activity Relationships.C. Glycine2 Structure-Activity Relationships .D. GlycineJ Structure-Activity Relationships . . .E. Phenylalanine4 Structure-Activity Relationships . . .F. Methionine5jLeucinc5'Structure-Activity RelationshipsG. The Enkephalin C-Terminus . . . . .H. Enkephalin-Based Opioid Antagonists. .Clinically Investigated Enkephalin AnalgesicsThe Chemical Anatomy of the EnkephalinsReferences .

459463463465468471471471473481482482484487490491496499499500502503

IV.V.

VI.

VII.VIII.

I. Introduction

While opium has been known for millennia and morphine for almost twocenturies, the discovery and characterization of the endogenous opioidpeptides have occurred only within the last decade. The discovery of theseendogenous opioid peplides was based on two main approaches thatoccurred after it was discovered that electrical stimulation of the peri-aqueductal gray region in rat brains produced naloxone-reversible analge-sia (1,2). In the first, the ability of various brain extracts to mimicmorphine's effect on mouse vas deferens and guinea pig ilium wasinvestigated (3). After demonstration of naloxone reversibility, purifica-tion of the active factor commenced (3). A second approach, utilizingbiochemical techniques, resulted in the identification of specific opiate-binding sites in brain tissue (4). Subsequently, three independent research

4\9

460 11 Enkephalins

groups reported their discovery of stereospecific opiate-binding sites withinthe central nervous system, the opiate receptor (5-7). Taken together, thefindings of naloxone-reversible analgesia after electrical stimulation andthe presence of opiate receptors in the brain allowed the conclusion that anendogenous opiate ligand must exist.

In 1975, several research groups demonstrated that pituitary and brainextracts contained compounds with opiate-like activity (3,8-10). Furthercharacterization by Hughes and Kosterlitz resulted in the successfulidentification of two pentapeptides: methionine-enkephalin (1) andleucine-enkephalin (2) (11). The isolation of these two pentapeptides,which differ only in their C-terminal amino acids, touched off an explosionin peptide-related research that has continued to this day and has resultedin the identification of various classes of opioid peptides.

Morley originally divided the opioid peptides into five categories(12,13). Now, however, the opioid peptides can be divided into endo-genous and nonendogenous groups that can be further subdivided(Fig. 11-1):

"

A. Endogenous peptides1. The two pentapeptides: [Met]enkephalin (1) and [Leu]enkepha-

lin (2).2. Peptides that arise, or are postulated to arise, from biosynthetic

enkephalin precursors. This type includes peptides arising fromadrenal proenkephalin: [Met]enkephalin-Arg6-Phe7 (3) (14),peptide E (4) (15), [Met]enkephalin-Arg6-Gly7-Leu8 (5) (16),dynorphin (6) (17), ex-and ~-neoendorphin (7) (18), and PH-8P(8) (19).

3. ~-Endorphin (9) (20,21) and the related ex- (10), y- (11), and 8-endorphin (12) (22-26). The terms endorphin and opioid pep-tide were used synonymously in early publications, and confusionresulted. Endorphins refer to those peptides which arise from~-lipotropin (27).

B. Exogenous peptides4. Pronase-resistant peptides. ~-Casomorphin-5 (13) and -7 (14) are

derived from amino acids 60-66 of the milk protein ~-casein (28).5. Dermorphin (15) and derived peptides. This potent antinocicep-

tive heptapeptide was isolated from the skin of South Americanfrogs of the Phyllomedusa species (29-31).

6. Various other peptides whose opiate-like properties do not arisefrom a direct receptor interaction. For example, the dipeptidekyotorphin (16) appears to act by releasing en kephalin (32).

I Introduction 461

Tyr-Gly.Gly.Phe-MetI ([Met)enkephalin)

Tyr-Gly-Gly-Phe-Leu2 ([Leu]enkephalin)

Tyr-Gly-Gly-Phe-Met-Arg-Phe Tyr-Gly-Gly-Phe-Met-Arg6 -Gly? _Leu")3 ([MetJenkephalin-Arg6.Phe7) 5 ([Met]enkephalin-Arg6-Gly7-Leu8)

I 5 W ~Tyr-Gly-Gly- Phe-Met-Arg-Arg- V al-GIY-Arg-Pro-Glu- Trp- Trp-Mct -Asp- Tyr-

20 25Gln-Lys-Arg- Tyr-Gly-Gly- Phe-Le~

4 (Peptide E)

1 5 W 15 17Tyr-Gly-Oly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln

6 (Dynorphin)

1 5 9Tyr-Gly-Gly-Phe- Leu-Arg-L ys- Tyr- Pro

7 (I3-Neoendorphin)

I 5 8Tyr-Gly-Gly.Phe-Leu-Arg-Arg- lie

8 (PH.8P)

I 5 10 15Tyr-Gly-Gly.Phe-Met -Thr-Ser-Glu- L ys-Ser.Gln. Thr. Pro- Leu. Val. Thr-Leu-

20 25 30 31Phe- Lys-Asn-A la-lie- lie. Lys. Asn. Ala- Tyr-Lys-Lys-Gly-Glu

9 (J3-Endorphin)10 (a-Endorphin, AA 1-16)11 (y-Endorphin. AA 1-17)12 (S.Endorphin. AA 1-27)

1 5 7Tyr-Pro- Phe- Pro-Gly- Pro-lie

tJ ({:f-Casomorphin-5, AA 1-5)14 ({:f-Casomorphin-7)

1 5 7Tyr- D-Ala-Phe-Gly- Tyr- Pro-Ser.NH2

IS (Dermorphin)

Tyr-Arg16 (Kyotorphin)

1 5 10Tyr-Gly-Gly.Phe-Leu-Arg-Lys- Tyr- Pro- Lys

17 (a-Neoendorphin)

1 5 10 13Tyr-Gly-Gly- Phe- Leu-Arg.Arg-Gln- Phe-Lys- Val- V al-Thr

18 (Rimorphin)

Fig. II-I. Opioid peptides

462 11 Enkephalins II Opioid Peptide Precursors 463

The various types of endogenous opioid peptides available from thethree types of biogenetic precursors are proopiomelanocortin (POMC),proenkephalin, and prodynorphin; these will be discussed in the section onen kephalin biosynthesis. Except for the following brief description of thebiological effects of the exogenous opioids, they will not be discussedfurther unless portions of the molecules were incorporated into theenkephalins. The casein-derived opioid l3-casomorphin-7 (14) has only 4%of the activity of [Met]enkephalin (I) in isolated guinea pig ileum (GPI)and 3% of the activity of morphine by intracerebroventricular (icv)administration (33). The dermorphins possess a unique D-alanine substitu-tion, hitherto found only in bacteria. Despite their recent discovery, anextensive structure-activity profile has emerged. Dermorphin (15) itself is40 times as potent as [Met]enkephalin (I) in the isolated GPI and 1000times as potent as morphine in the rat hot plate test by icv administration(34). The structure-activity results on a large number of derivatives haveindicated the following (35,36):

1. The N-terminal tetrapeptide is the minimum sequence required foropioid activity.

2. The three amino acid residues of the N-terminal are most importantfor activity.

3. Substitution of Gly4 retains activity.4. O-Methylation of Tyr1 retains activity (37), while O-sulfation de-

stroys it (38).5. Substitution of Tyr' and/or modification of the C-terminal are

readily tolerated.

The various classes of endogenous opioids have differing selectivities forthe J.I.,13,and Kreceptors. Derived pep tides and many synthetic analogs, somecontaining unnatural amino acids, have furnished ligands with very highdegrees of receptor-subtype selectivity, so that the biological properties ofthese subtypes can be more readily investigated. The minimum lengthnecessary for anti nociceptive activity in the enkephalins has been investi-gated, as well as the effects of this truncation on receptor, particularly J.I.and 13,selectivity. '

The structure-activity relationships among the individual amino acids inen kephalin have been resolved. However, the effect of multiple changes inenkephalins does not lend itself to the type of structure-activity reportingemployed for the rigid opiates. As a result, except for single amino acidchanges, the discussion of synthetic enkephalins with multiple changeswill be restricted to those that are biologically and especially clinicallyinteresting.

II. Opioid Peptide Precursors

The biosynthesis of the opioid peptides illustrates what appears to be atrend in neurobiology. Like many other central nervous system (CNS)peptides, the opioid peptides are not synthesized individually. Instead, asingle gene codes for a large inactive polypeptide that contains within itsstructure the sequences of several small active molecules that are subse-quently split from the precursor by processing enzymes. Often the indi-vidual active peptides perform different functions. Such an arrangementconfers a great deal of flexibility on the CNS. It may help to coordinate theseparate actions that combine to produce complex behavior. Moreover, ifthe sites where processing occurs vary from tissue to tissue, it will bepossible to generate different combinations of peptides from a single geneproduct. These possibilities have proved true for at least one of threeopioid polypeptide precursors. Three separate genes code for the opioidpeptide precursors. The first of the large precursors identified wasproopiomelanocortin, which contains a wide variety of other biologicallyactive peptide sequences. Subsequently, both proenkephalin and pro-dynorphin were identified. The biosynthesis of opioids has been exten-sively reviewed (39-45).

A. Proopiomelanocortin

Soon after the discovery of the two enkephalin peptides, the [Met]enk-ephalin sequence was found to be present as amino acid residues 61-65 of alarge 11,000-dalton polypeptide, l3-lipotropin (I3-LPH) (46), and a 3000-dalton fragment of I3-LPH, l3-endorphin (21). These larger peptides werepresent in appreciable amounts in mammalian pituitary glands (47,48)and were derived from a still larger polypeptide of about 31,000 daltons,proopiomelanocortin (or proopiocortin) (49-53). The gene coding forproopiomelanocortin (POMC) was rapidly cloned and sequenced, and theamino acid sequence is shown in Fig. II-2. (54).

The complete POMC molecule contains the amino acid sequences ofseven distinct biologically active peptides: l3-endorphin (residues 235-265), l3-lipotropin (residues 173-265), adrenocorticotropic hormone(ACTH) (residues 132-170), a-melanocyte-stimulating hormone (a-MSH)(residues 132-144), I3-MSH (residues 215-232), y-MSH (residues 77-88),and corticotropin-like intermediate lobe peptides (CLIP) (residues 149-170). The individual peptides in POMC are bounded on both pairs of basicamino acids, combinations of lysine and/or arginine, whose occurrence atstrategic sites of cleavage is typical of prohormones (55).

CI

II Opioid Peptide Precursors 465

POMC is made in the anterior and intermediate lobes of the pituitarygland, as well as in several other areas. Processing of POMC is different inthe anterior lobe of the pituitary of rodents than in the intermediary lobe.In the anterior lobe, the initial product is cleaved to produce ACTH and,B-lipotropin. The intermediate lobe also produces ACTH and ,B-LPH, butthese are immediately cleaved to produce a-MSH and CLIP, and ,13-endorphin and y-LPH, respectively (43).

The derived ,B-endorphin has reasonably high affinity for the /L (2.05-nm), jj (2.36-nm), and K (67-nm) opiate receptors (56). By icv administra-tion, ,B-endorphin has ISO times the potency of morphine as an analgesic(57). Apparently, the entire ,B-endorphin molecule is necessary for analge-sia, since deletion of only three amino acids from the C-terminal results in94% loss of the analgesic potency of ,B-endorphin (58). The [Metjenkepha-lin moiety in ,B-endorphin is critical for opiate activity, since removal of it,or even of the tyrosine I , eliminates analgesia (58,59). Several otherclassical amino acid substitutions in the ,B-endorphin amino acid sequencehave been reported, but without very significant positive changes inanalgesic potency (59). The presence of a free amino group on theN-terminus is critical to activity. N-Acetylated derivatives of ,B-endorphinare without activity (60). Amino acid extensions from the N-terminus alsoabolish acitivity, indicating that ,B-lipotropin does not have any directactivity at opiate receptors (61).

Initially, the presence of the [Met]enkephalin sequence in POMCindicated that [Met]enkephalin was derived from POMC via processingthrough ,B-lipotropin and ,B-endorphin. However, a series of studiesdemonstrated that it was doubtful that ,B-endorphin served as a precursorof en kephalin in the brain. First of all, brain levels of ,B-endorphin are onlyapproximately 5-10% those of the enkephalins (62). Also, the regionaldistributions of ,B-endorphin and the enkephalins differ substantially(62,63). It was necessary to look for additional enkephalin precursors thatwere structured to be processed to [Leu ]enkephalin, since POMC does notcontain this sequence. Furthermore, although the ,B-endorphin se-quence is preceded by a Lys-Arg enzyme cleavage sequence, the [Met]en-kephalin sequence is not ended by a recognized signal for proteolyticprocessing. Thus, the ,B-endorphin sequence is programmed to be pro-cessed out essentially intact from POMC and does not serve as a precursorto [Met]enkephalin. As a result, it was necessary to determine theprecursors and biosynthetic pathways leading to the enkephalins.

B. Proenkephalin

Since the question[Leu ]enkephalin had

of the nature of the precursor(s) to [Met] andnot been resolved with the characterization of

466 11 Enkephalins

POMC, the pituitary gland and the brain were examined for opioidprecursors using modern biochemical techniques (42,64). The peptideprecursors were present, however, in such low concentrations that asubstantial isolation effort would have been necessary. Fortunately, at thissame time, bovine adrenal medulla was found to contain high concentra-tions of opioid peptides (65). Among the many peptides isolated from thissource were enkephalins I and 2, C.terminal extended derivatives 3 and 5,and peptide E (4), as well as a large number of longer opioid-containingfragments. Peptide 3, containing C-terminus Arg6_Phe7, was considered tobe the terminating carboxyl end peptide sequence in the parentpolypeptide, since this dipeptide is not a processing signal for cleavage(66). Simultaneously with the work on peptide isolation, recombinantDNA techniques were being applied to characterize the enkephalinprecursor. The complete structure of the enkephalin precursor, proen-kephalin, was simultaneously announced by two independent researchgroups (Fig. 11-3) (54c,67,68). Human proenkephalin has also beensequenced (69). Tbe degree of homology between the two is very high,particularly at the protein level. Each contain six [Met ]enkephalin se-quences and one [Leu]enkephalin sequence, as well as peptide E (4) andthe C-terminal extended enkephalins 3 and 5. These peptides, except forpeptide E, are normal constituents of both adrenal chromaffin cells andbrain tissue (70). No peptides with other types of biological activity haveyet been identified in the proenkephalin molecule, as was found in POMC.

The receptor affinities for the various opiate receptor subtypes havebeen determined. Initial results for [Met]- and [Leu]enkephalins, usingGPI (p.) and mouse vas deferens (MVD) (~), indicated that both were ~selective, with [Leu]enkephalin being more ~ selective (71). A moresophisticated analysis using receptor-subtype selective ligands yielded theaffinities for the p., ~, and K receptors, as well as their relative affinity(Table 11-1). The earlier results were confirmed with [Leu]- and[Met]enkephalin being ~ selective, without any K affinity (71,72). Extend-ing the C-terminal by two (3) or three (5) amino acid residues yieldsenkephalins that are effectively equipotent at both the p. and ~ receptorsand possess some K receptor affinity (73,74). In this respect, they are verysimilar to the 31 amino acid peptide j3-endorphin (9) in their receptor-subtype profiles (56).

The analgesic activity of [Met]- and [Leu]enkephalin, by icv administra-tion jn a variety of antjnociceptjvetests, is either nonexistent or very weakand transitory (75). Similarly weak and transitory analgesia has beenobserved for 3 (76). A time study of the opioid effects on mouse tail flickanalgesia confirmed the lack of activity of enkephalins I and 2, while theC-terminal extended enkephalins 3 and 5 have 10 and 5% of the analgesic

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Receptor Affinity" (nm) Relative Affinity

Peptide"

S K " S K Reference

[Met]enkephalin (I) 9.5 0.9 4440 0.09 0.91 0 71 (:I[Leu)enkephalin (2) 19 1.2 8210 0.06 0.94 0 72(Met]enkephalin- 27 29 108 0.47 0.42 0.11 73

Arg'-Phe' (3)[Met]enkephalin- 6.6 4.8 79 0.41 0.56 0.03 74

Arg6_Gly7_Leu8 (5)

fJ-Endorphin (9) 2.1 2.4 67 0.52 0.46 0.02 56

a Receptor subtype ligands: J.L,(D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO); S, io-Ala2,D-Leu5]enkephalin (DADLE); K, bremazocine (see Chapter 6, compound 177).

468 11 Enkephalins

Table 11-1

Opiate Receptor Subtype Affinities for Proenkephalin-Derived Opioids and I3-Endorphin

potency of morphine. However, the activity peaked rapidly and was gonewithin minutes (77), Peptide E (4) was four times as potent as morphine,and this activity was present for at least 30 minutes (77), The lack ofanalgesic activity of enkephalins is due to their rapid enzymatic degrada-tion in the brain (78).

C. Prodynorphin

Determination of the structure of POMC and pro en kephalin did notaccount for two other [Leu]enkephalin-containing peptides that wereknown to be present in porcine pituitary glands and other tissues:a-neoendorphin (17) ({3-neoendorphin-LyslO) (18) and dynorphin (6)(59,79), Thus, at least one additional gene product had to be involved toexplain their occurrence. Research into the origins of these enkephalinsled to the discovery of a third [Leu]enkephalin-containing peptide, atridecapeptide, rimorphin or dynorphin B (18) (80), At the same time, a32-amino acid peptide, containing dynorphin at the amino end and thetridecapeptide at the carboxyl end, was isolated from pig pituitary (81),The common genetic origin of all of these [Leu]enkephalin-containingpeptides was convincingly demonstrated by cloning experiments (82),Sequencing of the cloned cDNA from porcine hypothalamus showed aprecursor that contains the complete sequence of dynorphin and a-neoendorphin but contains no [Met]enkephalin sequences (Fig, 11-4),The precursor polypeptide was originally termed proenkephalin B (82),although pronorphin has also been used (80), The most commonly usedand least confusing name is, however, prodynorphin (81), Analysis of thecDNA structure indicates that prodynorphin consists of 256 amino acids,

Table 11-2

Opiate Receptor Subtype Affinities for Prodynorphin-Derived Opioids

Receptor Affinity (om) Relative Affinity

Peptide"

5 K " 5 K Reference

a-Neoendorphin (17) 1.24 0.57 0.20 0.10 0.23 0.67 84(3-Neoendorphin (7) 6.9 2.1 1.2 0.10 0.33 0.57 73Dynorphin (6) 0.73 2.4 0.12 0.13 0.04 0.83 84Dynorphin 1-8 3.8 5.0 1.3 0.22 0.16 0.62 84Rimorphin (18) 0.68 2.9 0.12 0.14 0.03 0.83 73

470 11 Enkephalins

including a putative signal sequence of 20 amino acids. Prodynorphincontains three repeating [Leu ]enkephalin sequences, two of which repre-sent the N-termini of the neoendorphin (residues 175-183) and dynorphin(residues 209-225) sequences that are flanked by Lys-Arg couplets. Thethird enkephalin sequence, leumorphin (residues 228-256), is connectedby paired arginine residues to a 22 amino acid C-terminal sequence (seeFig. 11-4).

There is remarkable homology between the two enkephalin precursors,proenkephalin and prodynorphin, within the N-terminal region. Bothpossess shared amino acid residues at equivalent positions, and bothpossess six cysteine residues at almost identical positions following thehydrophobic signal sequence. Disulfide bond formation and protein fold-ing probably play an important role in the processing of thesepolypeptides.

While processing of POMC and proenkephalin produce peptides thatare analgesic, similar processing of prodynorphin does not produce anyknown analgesic peptides (78). For instance, a-neoendorphin (17), dynor-phin (6), dynorphin 1-8, and rimorphin (18) are all inactive in the mousetail flick assay after icv administration (78,83).

The opiate receptor-subtype affinities for prodynorphin-derived peptidesare presented in Table 11-2 (84,85). In the prodynorphin series, theoutstanding observation is the high affinity for the K binding receptorsubtype for the five endogenous peptides. That dynorphin (6) was aselective endogenous ligand for the K receptor was established by bioassayas well as binding studies (86). Both dynorphin (6) and rimorphin (18)have very high affinity for the K site, whereas that of a-neoendorphin (17)is not quite as high. Dynorphin 1-8 and /3-neoendorphin (7) have thelowest K affinity of the five peptides. At present, it is not possible to assessthe physiological significance of these peptides, since, in spite of their highK selectivity, they still have significant affinities for the J.I.and

{j receptor

sites (85).

III Peptide Synthesis471

III. Peptide Synthesis

t

A. Amino Acid Protecting Groups

A peptide is the formal result of the condensation of amino acids withthe elimination of water. If the reaction is to give a single product, therehas to be only one free amino group and one free carboxyl group,necessltatlOg protectIOn of the functIonal groups that are not involved inamide bond formation. The situation is complicated by the presence ofreactive functional groups in the amino acid side chains that also requireprotectIve blocklOg groups. Thus, two types of protective groups areneeded: one type that intermittently protects the a-amino and carboxylgroups and liberates them again selectively, and a second type that blocksthe other functional groups throughout the synthesis. For a protectinggroup to be useful, it must be (a) easily introduced, in high yield, intoamino acids and peptides, (b) completely stable during peptide bondformation, and (c) quantitatively removable without deleterious effects onthe peptide. Although many protective groups have been described, only afew have found general and extensive use. Since most peptides arereasonably stable in acidic media, combinations of protective groupshavlOg graded acid labilities are preferred. Only a few other methods ofcleavage are used, notably reductive ones. An in-depth appraisal ofprotecting groups for amines (87), carboxyl (88), sulfhydryl (89), andhydroxyl (90) residues in peptide synthesis has appeared. Dual functionalprotecting groups (91) and differential protection and selective deprotec-tion (92,93) have been reviewed, as well as peptide synthesis with minimalprotection of the side chain functions (94). The preceding subjects havealso been reviewed in Hoube'n-Weyl (95).

B. Methods of Amide Bond Synthesis

1. Solution Methods The high demand for efficiency in peptide amidebond formation has restricted the number of generally useful methods. Tobe useful, a good method must provide (a) a very low to nonexistent rate ofracemization (96), (b) minimal side product formation, (c) facile workup,(d) high to quantitative yields, and (e) reasonable rates of reaction. Themost important requirement is the absence of racemization because thebiological activity of the peptides is invariably dependent on their con-figurational integrity, and removal of unwanted isomers can be extremelydifficult (97). No known method meets all these requirements, and so faronly four methods have been found to be sufficiently effective for generalsynthetic use. The methods are (a) the azide method, (b) mixed anhy-drides, (c) dicyclohexylcarbodiimide condensations, and (d) active esters.

472 11 EnkephalinsIV Enkephalin Selectivities for the IL and 8 Opiate Receptors

473In the azide method (98), an activated carboxyl component is pre-

pared in two stages: the formation of N-protected amino acid or peptidehydrazides followed by conversion to the aZIde pnor to couphng wIth acarboxyl protected amino acid. Azide couphngs were ongmally consId-ered to be free of racemization, but substantial racemizatIOncan occurparticularly with larger peptide fragments (96,~9.1. The second method,mixed carbonic carboxylic anhydrides (100), utthtzes the reactIOn of anN-protected amino acid with a chlorocarbonate ester in the presence ofa weak tertiary base. The mixed anhydride thus formed IS treated m situwith the amine component. The method is valued for ItS rapId reactIOnsand facile workup. In the dicyclohexylcarbodiimide method, th~ car-boxylic acid is activated by addition across one of the carbodnmldedouble bonds and in situ reaction with an amine component (101). ThIsmethod is used extensively in solid phase synthesis. In the active esterapproach, an ester of the N-protected amino. acid is formed with ahydroxy lie function that also serves as a facIle leavmg group uponreaction with an amine. This method ISdlstmgUlshed by the large vanetyof esters that have been found suitable (102). The potential for theoccurrence of side reactions in the various methods of peptide synthesishas been reviewed (103).

. .All of the preceding reactions are used in classical solutIOn peptIde

synthesis using two approaches (104). The first IS mcremental chamelongation wherein one amino acid at a time is added startmg from thecarboxyl-terminal end. The second is a convergent fragment approachwhere-in sequential fragments of the peptide are formed and ulttmatelyassembled using conventional techniques. Fragment condensatIon allowsgreater flexibility in the choice of protecting groups. The homogeneIty ofintermediate fragments can also be ascertamed. The drawbacks of frag-ment condensation are the potential for low solubility of the largerfragments, slow coupling rates, and increased potential for racemizationand intramolecular reactions.

2 The Solid Phase Method A major problem with peptide synthesisis that it is very labor intensive, primarily in the workup and purificationof the intermediates. A partial solution to this problem IS the sohd phasemethod, which is based on the incremental addition of amino acids to agrowing chain, which is utilized extensively in solution techniques. How-ever, in this case, the carboxyl-terminal end of an ammo aCId ISattached toan insoluble support resin. Because the growing peptide is covalentlybound to a polymeric support, the product is readily separated from theby-products. Each coupling step of the polymer-supported peptIde chamcan be driven to completion through the use of excess soluble reagents, and

mechanical losses are diminished by retaining the peptide-polymer beadsin a single reaction vessel. The most attractive features of the solid phaseapproach are as follows: (a) there is high-speed attachment of severalamino acids per day to the peptide chain, (b) insolubility problems that cantrouble solution syntheses of larger peptides are avoided, (c) the procedureis easy and convenient to perform, and (d) mechanization and automationsubstantially reduce the labor commitment. The major drawback to thismethod is the extensive purification of the final product that is necessarydue to the slightly less than quantitative yields in each coupling step. Thestrength of the solid phase method lies in its operational efficiencycompared to product quality, which is the strength of conventional solutionmethods. The solid phase method has been critically reviewed byMerrifield (105).

IV. Enkephalin Selectivities for the JL and i5 OpiateReceptors

At approximately the same time that basic structure of the enkephalinswas determined, the existence of various subtypes of opiate receptor waspostulated by Martin on the basis of his extensive reseearch on the chronicspinal dog (106). These were designated J.l.,K, and u. Subsequently, afourth subtype, 8, was proposed, which had a relatively high affinity for theenkephalins (cf. Chapter 2) (107). The occurrence of multiple receptorsubtypes offers the potential for design of specific compounds targeted foreach, with, it is hoped, a specific biological profile resulting. The design ofreceptor-subtype specific ligands has resulted in some highly selective, butnot completely specific, agents. The subtypes important for analgesia arethe J.l.,8, and K receptors. With extended-length enkephalins, dynorphins,and endorphins, K receptor occupancy becomes important. However, withthe pentapeptide and smaller enkephalins, only J.l. and 8 receptor selectivi-ties usually have to be considered. The following section will thereforeconcentrate on the effects of peptide chain length and C- and N-terminalsubstitions on J.l.and 8 opiate receptor-subtype selectivities, followed by adiscussion of the various subtype receptor ligands, including cyclic pep-tides, that have been developed. In the following tables, where potenciesare referred to GPI and MVD, GPI represents the potency of thecompound in the electrically stimulated guinea pig ileum, a tissue prepara-tion considered to be rich in J.l. receptors. MVD refers to potency in themouse vas deferens, a tissue rich in 8 receptors. In both cases, [MetJen-kephalin is defined as having a potency of I.

474 11 Enkephalins

Table 11-3

The Effect of Enkephalin Chain Length and C-Terminal Substitution on 1J.and 5Receptor Selectivities

Peptide GP[ MVD GPI/MVD Ratio References

[LeuJEnk 0.36 1.2 0.3 108[MctJEnk 1 1 1 109[D-Ala2,Leu5]Enk 5.5 9.U 0.6 I/O[D-Ala2,Met5]Enk 6.3 5.0 1.2 III

I.14 7.2 0.16 1/2[D-Ala2,Lcu5]Enk-OMe 5.6 3.0 1.9 1/2.1/3[D.Ala2,Met5]Enk-OMe 4.2 2.9 1.4 1/2.1/4[1)-Ala2,Leu5]Enk-NH2 5.0 1.6 3.[ 1/1[D_Ala1,Mct5]Enk. 3.3 2.5 1.3 1/5NH,(DAME)Tyr-D-Ala- Phc-Mct -NH2 1.2 0.056 2[ 1/6Tyr-n-Ala- Phc-Lcu-NH2 1.2 0.054 22 1/6Tyr-D-Ala-Phe-NH2 0.11 0.002 55 1/7

25 1 25 1/6Tyr'D-Ala-Gly- 1.3 0.04 32 71NH(CH,j,C,H,Tyr-Phe-Met-NHz 0 0 1/6Tyr'D-Ala-NH( CHzhC(,lls 0.008 U.0U6 [3 1/6Tyr-n-Ala-NII( CI12hC6Hs 7.7 U.U13 59 116Morphine 1.34 U.U3 48 109

GP[" MVD" GPI/MVD Ratio

2.2 0.26 8.54.4 0.18 24U.32 <O.O[ -320.62 <O.Ul -62

IV Enkephalin Selectivities f(Jr the JL and 5 Opiate Receptors 475

Table 11-4

The Influence of Phe4 on JL: /) Opiate Receptor Selectivity

Peptide

19 Tyr-D-Ala-Gly-Phe

20 Tyr-o-Ala-Gly-NH (CH,hC,H,21 Tyr-o-Ala-G[y-NH-CH(CH,)CH,CI[(CH,h22 Tyr-o-Mct -Gly-NH-CH (CII,)CH,CH( CI I,h

'"Relative to [Met]enk = 1.

selectivi[y again predominates. In this case, however, the phenylpropyla-mide may be substi[uting for [he phenylalanine side chain. Deletion ofboth Gly2 and Gly3 elimina[es any ac[ivity in the tripep[ide Tyr-Phe-Met-NHb indicating that [here is a critical distance between the [yrosine andphenylalanine aromatic rings. The dipeptides, con[aining Tyr-D-Ala andwith a phenylpropylamide or a phenylethylamide C-terminus, retainsurprisingly po[ent activity thaI again is IJ. selec[ive.

A dramatic effect on IJ.:{jselectivity involves the influence of Phe4 (Table11-4). Early work by Kosterlitz (1/8) indica[ed a substan[ial IJ.selectivitywhen the C-terminal in [Leu]enk is decarboxyla[ed. Independently, othersinvestigated the effect of changing Phe4 to nonaromatic lipophilic groups.The [etrapep[ide (19) is IJ. selective, as is its decarboxylated analog (20).However, a decisive shift towards IJ.receptor specificity is obtained whenthe phenethyl group (20) is changed to [he strictly aliphatic hydrophobicside chain in 21. This change between 20 and 21 leads to a large decreasein {j receptor recognition. The IJ.-selectivity is fur[her enhanced by [hesubstitution of D-Me[2 for D;Ala2, perhaps reflecting a better binding a[ thelipophilic auxiliary site (1/9).

Since dihydromorphine is a pro[otypic rigid opiate ligand for the IJ.recep[or, it was not surprising that various physical chemical investigationsprobed the similarities between the rigid opiates and the p.-selectivepeptides (120). The resulIs of a series of s[udies (7/ ,/21) employing,among others, pep tides 21 and 22, using both NMR investigations andconformational energy minimization techniques, have led to severalconclusions:

Table 11-3 demonstrates the effect of both C-terminal substitution andamino acid chain leng[h in IJ. and 8 receptor selectivities. In Table 11-3 aGPI/MVD ratio of less than I indicates 8 selectivity and a ratio of greaterthan I, IJ. selectivity. All responses are related to [Met]enkephalin.[Leu ]enkephalin is more 8 specific than [Met ]enkephalin. Replacement ofGly2 with D-Ala2 in bo[h enkephalins resulIs essentially in re[en[ion of thesame rela[ionships. However, comparison of the resulIs from two differentlaboratories for [D-Ala2,Met5]enk demonstrates both the uncertaintiesand dangers in comparing data from different investigators. SinceD-Ala2 is a very common substitution, the comparisons in Table 11-3 arebased on enkephalins with this substitu[ion. However, incorporation oflipophilic D-amino acids in the second position increases IJ. recep[orselectivity, apparently [hrough an auxiliary binding site (71 ,110). Conver-sion of the C-[erminal carboxylic acid of [he enkephalins to ei[her ester oramide results in an increase in IJ. specificity, especially for the amides.Deletion of Gly3 to form the tetrapep[ide amides analogous [0 thedermorphins and casomorphins strongly increases IJ. specifici[y. In the[ripeptides, where the C-[erminal is subs[i[u[ed by a phenylpropylamide, IJ.

I. Due [0 [heir small size and hydrophobic content, these peptides areable to fir [he conformational space occupied by the morphinealkaloids.

2. The peptides exist in a highly folded conforma[ion, suggested by thepoten[ morphinomimetic activi[y of conforma[ionally constrainedanalogs incorporating a-aminoisobutyric acid (Aib2) (/22).

416 II Enkephalins

3. The folded conformation is within the approximately 5 kcal/mole ofenergy available to the lowest-energy peptide conformation in solu-tion at room temperature.

4. There is external orientation of the lateral side chain of any o-aminoacid at position 2, but not for their L-enantiomers. This allows anadditional bonding interaction at a lipophilic binding site on thereceptor.

5. There is a good, energetically feasible overlap between the tyrosineand the phenethyl chain of morphine. This obviously also occurs forpeptides specific for the 0 receptor.

6. There is similar spatial orientation of the C-6-a-hydroxyl group ofmorphine and the critically important amide carbonyl group of Gly3(119,123).

Circular dichroism studies also confirmed the existence of folded con-formations for the J1.,but not the 0, selective peptides (124).

In summary, specificity for J1.opiate receptor binding sites is obtained by:

1. Decreasing the number of amino acids in the enkephalin chain.2. Increasing the lipophilicity at the C-terminal by esterification, amide

formation, and especially decarboxylation.3. Replacement of the aromatic Phe4 residue with a lipophilic aliphatic

side chain.4. Introduction of a hydrophobic o-amino acid as the second en kephalin

amino acid.5. The use of hydrophobic amino acid as the fifth residue to occupy an

additional receptor-binding site.

This summary, although somewhat oversimplified, explains much of theobserved biology. Additionally, the J1.selectivity derives not from anincrease in J1.receptor affinity but from a drastic reduction in affinity for theo receptor.

An exception to the above observations is the tetrapeptide morphiceptin(23) (125), which is a derivative of the exogenous opioid l3-casomorphin(126). Morphiceptin (23) is reported to have an affinity for the J1.receptorthat is 1000 times greater than that for 0 receptors, hence its name (126).Although the presence of proline as the second and fourth amino acidsdoes involve significant conformational restrictions, replacement of Pro2by o_Pro2 effectively eliminates biological activity. Morphiceptin hasanalgesic effects when administered icv (I27), and limited structure-activity relationships have been developed (128). Disparate results fromanother laboratory (129), however, need to be resolved before morphicep-tin can be considered as a J1. receptor opioid ligand. The second

IV Enkephalin Selectivities for the Jl and 8 Opiate Receptors411

1

laboratory investigated l3-casomorphins ranging from four to seven aminoacids in length and reported only a fourfold selectivity of 23 for the J1.receptor (129).

The reduction of the C-terminal carboxylic acid to the correspondingalcohol, an effect designed to change a hydrophilic group into an essential-ly lipophilic one, has led to very J1.-selective ligands. For instance, thetetrapeptide (24), syndyphalin or SD-25 (130), possesses a hydrophobico-amino acid at position 2 and backbone methylation between Gly3 andPhe-oI4, as well as having the usual Phe4 present as phenylalaninol (131).The changes result in a peptide that has parenteral analgesic activity more

Try-Pro- Phe-Pro-NH2 Tyr-o-Met( O)-Gly-MePhe-ol23 (Morphiceptin) 24 (5yndyphalin. 50-25)

Tyr-D-Ala-Gly-McPhe-Gly-ol Tyr-D-Ala-Gly-MePhe-Met(O)_ol25 (DAGO. glyol) 26 (FK33-824)

potent than that of morphine (132). Syndyphalin (24) is significantly moreJ1. selective than morphiceptin (23) and displaces tritiated dihydromorphine(ICso, 0.05 nm) much more effectively than DADLE (33) (ICso, 200 nm)(133). The current prototypic opioid ligand for the J1.receptor is thepenta peptide 25 (DAGO or glyol), where again the terminal amino acid'scarboxyl group, in this case Glys, has been reduced to the alcohol (134).Glyol (25), with a selectivity of lOa for the J1.over the 0 receptor, is thus abetter J1.ligand than the rigid opiate normorphine. The effects leading tohighly J1.-selective ligands are finely balanced. For instance, retaining thefirst four amino acids in DAGO (25) and replacing the ethanolamineC-terminus (glycine alcohol) with methionine sulfoxide alcohol (Met(O)-ol)results in the pentapeptide 26 (FK-33-824), a very potent morphine-likeanalgesic peptide (135). This peptide has in its structure all of the criticalcomponents necessary to interact with both J1.and 0 receptors. It exhibitshigh potency in both the GPI and MVD assays and inhibits equally wellboth rigid opiate and opioid binding in brain homogenates (1I8).

Among the approaches to the preparation of J1.'selective ligands, basedon the concept of a folded peptide conformation, is the formation of cyclicenkephalins. Cyclization in en kephalin analogs is particularly powerfulway to reduce drastically the conformational degrees of freedom. Asuccessful approach has used the formation of cyclic lactams between basico-amino acids in position 2 and C-terminal carboxylic acid (120)_ Since inthese structures Tyrl is exocyclic, the necessary flexibility in this region ismaintained. The initial compound (27) containing a 14-membered ringlactam incorporates 0-2,4-diaminobutyric acid as the bridging ligand.Compared to [Leu]enk (2), 27 is 17 times more potent in the GPI assayand 7 times less potent in the MVD test. Confirming results were obtained

Compound"

GPI" MVD" GP!iMVD Ratio

27 2 10.5 0.16 5.8

29 1 17.5 U.14 3.1

30 3 5.1 0.02 9.9

31 4 51.2 O.OS 2tiA

28' 10.6

478 II Enkephalins

Table 11-5

Lactam Formation in Pentaenkephalins

o H

TYr-~~~-:nN(CH,I, 0

N'-N HH

o

" Relative to (Leu]enk (2) = 1.f> (28) = Tyr-D-Nva-Gly-Phc-Lcu-NHz (Nva = norvaline)

in receptor binding assays (136). Comparison with the correspondingopen-chain analog 28 demonstrated that the IL-receptor selectivity of 27is a direct result of conformational restriction, confirming the previouslydiscussed physicochemical conclusions derived from flexible peptides(137). Some variation in conformational restriction was achieved byvarying the number of methylene spacing groups in the basic amino acid2(13B). All of these analogs showed wreceptor selectivity (Table 11-5) withselectivity increasing with lactam ring size, 13-membered through 16-membered. When compared to [Leu]enk (2), the most active analog 31 is51 times more potent in the GPI assay and 12 times less potent in the MVDassay. The results of further structure-activity relationship studies indi-cated that these cyclic analogs possess the same configurational require-ments in amino acids I, 2, 4, and 5 as the linear enkephalin (139).

A second class of cyclic wselective ligands was obtained by substitutionof cysteine at positions 2 and 5 and subsequent ring formation throughdisulfide bond formation. The initial example (32) was a surprisingly stronganalgesic by iv administration and possessed substantial respiratory de-pression properties. It was 100 times more potent than morphine incompeting for its receptor (140). A subsequent investigation employing[D-Cys2,D-CyS']- and [D-Cys2, Cys']-enkephalins revealed that these cyclic

IV Enkephalin Selectivities for the Jl. and 5 Opiate Receptors 479

disulfides were nonselective toward the ILor 8 receptors (141). However,use of penicillamine (13.I3-dimethylcysteine), which couples the conforma-tional constraints of aminoisobutyric acid and disulfide ring formation,generates highly 8-specific peptides.

The peptide usually considered the prototypic 8 receptor ligand isDADLE (33), an analog of [Leu]enk where Gly2 has been replaced byD-Ala2 and Leus is present as its D-Leu' enantiomer (liB). However,DADLE (33) possesses only a threefold preference for the 8 receptor(142). Since lipophilic D-amino acids at position 2 enhance IL selectivity, ahydrophilic group at this position could be expected to enhance 8 selectiv-ity. Additionally, since decreasing chain length favors IL selectivity,increasing it slightly may enhance 8 affinity. Empirically, it was found thatreplacement of Gly2 with the hydrophilic Ser2 and introduction of Thr6 in[LeuJenk furnished a peptide (34) (DSLET) that is 620 times more potentin the MVD assay than in the GPI assay and is about 10 times more specificfor 8 receptors than DADLE (33) (71.143). The replacement of Ser' in 34by Thr2 yields the even more specific deltakephalin (DTLET) (35).Deltakephalin (35) has a 3000-fold separation of activities between the GPI

S SI I

Tyr-D-Cys-Gly- Phc-n-Cys- N H 232

Tyr-D-A !a-Gly- Phe-])- Leu

33 (DADLE)

Tyr- Y -Gly-Phe-Leu-Thr

34 (Y ~ Scr. DSLET)35 (Y = Thr, deltakcphalin, DTLET)

i

and MVD assays (144). These results indicate the importance of either thehydrophilicity or lipophilicity of the second amino acid in enkephalin. Theimportance of Phe4 for 8 selectivity was again underscored by the larged~crease in MVD potency when it was replaced by hexahydrophenylala-mne (145). Another striking result is the high degree of 8 specificityencountered when the fifth amino acid is replaced by its D-enantiomer.However, this effect is reversed by the addition of threonine as the sixthamino acid (146). These differences probably reflect the ability of Phe4 tofit into its 8-specific binding site (71).

On the basis of both the IL and 8 ligand investigations (71), 8 opiatereceptor specificity is engendered by:

1. The presence of an aromatic ring at the equivalent position ofphenylalanine at position 4.

Compound X Y GPI MVD GPljMVD ratio

36 D-Pen D-CyS 1350 6.3 2t537 ()-Pen Cys 213 0.3 66638 D-Pen D-Pen 6930 2.2 316439 D-Pen Pen 2720 2.5 t08840 D-CyS D-Pen 67 0.t3 51541 D-CyS Pen 40 0.75 53

Mode ofAdmin. References

icy 145,154icy 145,153

154154

sc 155,156icy 116,157sc 158sc 158

48(1 11 Enkephalins V Minimum Enkephalin Chain Length Necessary for Analgesia 481

2. The presence of a hydrophilic C-terminus that allows the Phe4aromatic ring to be fitted into its 8-binding site. That is, the aminoacids following Phe4 playa key role in determining /j specificity.

3. The presence of a hydrophilic side chain on the second amino acid,such as Thr or Ser, strongly enhances /j specificity.

4. An extended, rather than folded, energetically available conforma-tion of the peptide.

While the necessity of extended peptide conformations of enkephalin for/j receptor selectivity has enjoyed considerable support, the emergence ofan entire class of cyclic 8-specific peptides indicates that the extended formconcept may have to be modified. Although cyclic [o-Cys', 0-, or L-Cys5]enkephalins (e.g., 32) were only slightly JJ.selective (141), replacement ofcysteine with penicillamine (Pen, 13,I3-dimethylcysteine) ultimately led tothe most 8-specific pep tides currently known. Although the initial experi-ments were performed on the Pen-containing enkephalin amides (147), thefree acid was found to be more selective, in line with the precedinggeneralizations. Replacement of O-Cys2 in 32 with o-Pen2 yields a highly8-seleetive analog (36) (Table 11-6) (148), and even higher selectivitieswere obtained when penicillamine was introduced into positions 2 and 5.The eyclic [o-Pen2,o-Pen'J analog (38), having over a 3000-fold selectivity,is the most selective /j ligand known (149). This /j receptor selectivityprobably results from additional conformational rigidity in these cyclicanalogs imparted from the gem-dimethyl groups of Pen. An NMR study ofboth the cyclic cystine and penicillamine analogs indicated similar overallpeptide conformations. However, differences in conformation and flexibil-ity were observed at the C-terminal, which may account for the receptoraffinity differences in these analogs (150).

Another approach, which has also been used in the rigid opiates, is theformation of dimeric enkephalins linked by spacer groups of varyinglength. Among the dimers of a tetrapeptide, the one with a 12-methylenebridge unit (42) has optimum selectivity and affinity for /j receptors(151,152). The /j selectivity of 43 is approximately four times that ofDSLET (34). It has been suggested that the selectivity observed with thesedimers is the result of cross-linking of receptors by the two linkedindividual en kephalin terminals (151).

Tyr-D-Ala-Gly-Phe-NHI

(CH,)"ITyr-D-Ala-Gly-Phe-NH

42

V. Minimum Enkephalin Chain Length Necessary forAnalgesia

While [MetJenkephalin and [Leu]enkephalin do not demonstrate anal-gesic activity, due to their rapid inactivation by peptidases, the substi-tution of Gly2 by o-Ala2 in the enkephalinamides 43 and 44 (Table 11-7)restores analgesic activity to these molecules (145,153). The questionthen was what was the minimum chain length necessary for analgesia. Aseries of deletion peptides has been prepared to investigate this point, and

Table 11-'

Table 11-6Minimum Enkephalin Chain Length Necessary for Analgesia

b-Selective Ligands Based on Cyclic Penicillamine-ContainingPcntacnkephalins

Analgesia"

49 Tyr-o-Met(O).PPN

0.60.5

<0.020.05

0.6

Peptide Tail Flick Writhing

s sI I

Tyr-X-Gty.Phe-Y.OH

43 Tyr-o-Ala.Gly-Phe.Met.NH,

44 Tyr-D-Ala-Gly-Phe-Leu-NH2

4S Tyr-o-Ala-Phe-Met-NH2

46 Tyr-D-Ala-Phc-Leu-NH2

47 Tyr.o.Mct(O)-Gty-MPA'

48 Tyr-o-Ala-PPAc

0.51.4

a Relative to morphine = 1 (AD50 = 80 nmole/kg).toMPA = N-methylphenylethylamide.C PP A = 3-phenylpropylamide.

VI Structure-Activity Relationships in the Enkephalins 483

Table 11-8

N-Terminal Substitutions in EnkcphaJins

X.Tyr.Gly.Gly.Phe.Y

Compound X Y GP] MVD References

] H Met 1.0 1.050 CH) Leu 0.76 0.75 112.113.16351 CH., Met 1.0 0.2 111.16452 n-C3H7 Met 0.045 0.(108 16853 n-C:,;HH Met 0.67 0.01 16854 (CH,j, Leu 0.08 0.02 112.11355 CH,CO Leu <0.001 11356 (CH,j,CCO,(BOC) Leu 0.002 11359 Tyr Met 0.15 0.28 J0860 Phe Met 0.18 0.50 J0861 Arg Met 0.17 0.22 J0862 Lys Met 0.20 0.25 10863 Gly Met 0.30 0.18 J08

482 11 Enkephalins

some of the results are presented in Table 11.7. Tetrapeptides 45 and 46also retain analgesic properties (154). However, while both the tripeptide47 and the dipeptides 48 and 49 possess potent analgesia by icv administra.tion, they are also active as analgesics by parenteral administration(155-158). However, in pep tides 47-49, the arylalkylamtde groups at theC-terminal appear to be necessary for analgesIc actIvIty. It may be that thearomatic ring in the amide function substitutes for the aromatic ring inphenylalanine in [Met]. and [Leu]enkephalins. In summary, the analgesicproperties of the enkephalins parallel the activities fou.nd to be necessaryfor activity in the GPI and MVD assays, and the mInImum cham lengthnecessary for enkephalin.based analgesia is a dipeptide.

VI. Structure-Activity Relationships in the Enkephalins

The development of structure-activity relationships in the enkephalinarea began shortly after the disclosure of the structures of the endogenousopioids. Literally thousands of analogs have been prepared, and reviews ofthis structure-activity relationship have been published (12,159-160). Inthe majority of,cases, biological activity was primarily expressed in termsof the GPI and MVD bioassays. While these assays indicate the potentialfor analgesic potency, the effects of transport, metabolism, and tissuedistribution are not addressed. Keeping these facts in mind, the structure-activity relationship of the enkephalins will be indicated primarily on thebasis of MVD and GPI assays. The approach used will focus on each aminoacid in the pentapeptide. C. and N.terminal effects will also be indicated.The structure-activity relationship results will be primarily restricted to thepentapeptides, although tetrapeptides will be included. Additionally, onlysingle replacements will be considered, although common replacements,such as D.Ala' and D.Met', will be considered as equivalent to Gly' instructure-activity relationship discussions. Opioid analgesics related to thecasomorphin and dermorphin series will not be discussed; neither will theextensive investigations conducted on the isosteric amide bond replace.ments in the enkephalins (161). Effects of the enkephalin analogs onreceptor selectivity have already been discussed in Section IV and will notbe differentiated in any discussion of the analgesic effect, although the GPIis rich in I-' receptors and the MVD in S receptors.

amino acids. Removal of the amino group and replacement of Tyr' with4.hydroxyphenylpropionic acid results in the elimination of biologicalactivity in both [Met]. and [Leu)enkephalin (113,162). N.Methylation ofthe Tyr' in both [Leu]enkand [Met)enk results in little change in potencyin the GPI assay. While the [Leu]enk derivative (50) is equipotent in boththe GPI and MVD assays, the corresponding [Metlenk derivative (51) isfourfold less active in the MVD assay than is the GPI (Table 11.8). Theesters and amides of [Leu ]enk also show about a 4. to JO.fold reduction inactivity in MVD when compared to the GPI results (112,113,163,165). Aseries of n.alkyl substituted [Met]enk derivatives from ethyl through octylshows substantial decreases in potency and receptor affinity (168). Theseries peaks at n.pentyl (53), which has two. thirds the GPI activity of[Met ]enk, but vanishingly small MVD activity. Interestingly N ,N.dimethylation of the amino group (54) in [Leu]enk causes a markeddecrease in potency in both assays (112). Substitution by classical rigidopiate antagonist substituents will be considered in Section VI,H. Manyderivatives of enkephalins having the N.terminus blocked by acyl groups orcarbonates are intermediates in the total synthesis of the parent unblockedmolecule. These blocked derivatives 55 and 56 of [Leu]enk are essentiallywithout biological activity, indicating the need of a functioning N.terminalamino group, either mono or unsubstituted, for opioid activity. It has beenproposed that the opiate receptor has a region that prefers a cationicspecies in the area of tyrosine and that this region is restricted to 3.3 A

A. The Enkephalin N-Terminus

The amino group of tyrosine has been modified in a variety of ways: byacylation, alkylation, deamination, and extension by addition of other

X-Gly-Gly-Phe-Y

Compound X Y GPI

] Tyr Met 1.064 Phe Met 0.00265 Tyr(Me)" Met 0.1766 p-NII,Phe Met <0.0167 p-CIPhe Met <0.0168 p-IPhe Met <0.0169 3,4-(OIl),Pheb (DOPA) Met <0.0170 p-OH-phenylglycine Leu 0.0027] p-homoTyr Leu72 Gly Met Inactive73 Ala Met Inactive74 D-Ala Met Inactive75 His Leu <0.0002

484 11 Enkephalins VI Structure-Activity Relationships in the Enkephalins


N-Terminal Guanidine Substitutions Tyrosine Substitutions

Compound

0.04

MVD" Ratio

485

MVD References57 Tyr-D-Met-Gly-Phe-NII,58 II,N-C-Tyr-D-Met-Gly-Phe-NII,

IINil

1883

0.160.80

112104

1.00.00030.004

"[Met]enk ~ I.

(166). As a result, a series of strongly basic guanidino analogs ofenkephalins, exemplified by 58, containing D-Met2 in the tetrapeptideamide, have been prepared with the expectation that the more basicguanidino residue would result in an increase in potency (167). In general,this substitution substantially increases potency in both the GPI and MVDassays, with no general change in selectivity. The guanidino peptide (58) istwice as potent as the amino peptide (57) and 4.4 times as potent asmorphine by iv administration in the rat tail flick assay (Table] ]-9) (167).

Initial reports on the addition of amino acids to the N-terminal (169),indicated that ArgO, residue 60 of {3-lipotropin, maintained 90% of the GPIactivity of (MetJenk. In contrast to this earlier work, two other groupsobserved that even ArgO substantially lowered GPI potency (108,170). Avariety of lipo- and hydrophilic amino acids (59-63), possessing basic andacidic groups, all lower both GPI and MVD potencies without a noticeablechange in selectivity (Table] ]-8) (108). Increasing the chain length of theamino acids at the N-terminal causes the GPI potency to decrease rapidlyas the chain is extended (169). A series of analogs of [Met ]enk containing(3-alanineo, GABAo, and 5-aminopentanoic acido all lack activity in boththe GPI and MVD assays, as well as having minimal opiate receptoraffinity (171).

On the whole, most substitutions of the N-terminus decrease potency.N-Methylation can maintain, or slightly enhance in some cases, the bio-logical activity. There appears to be very little opportunity for manip-ulation of this portion of the en kephalin molecule.

162164,174159159159159JJ3JJ2159159159JJ3

" O-Methyltyrosine.b 3,4-Dihydroxyphenylalanine.c 2-Amino-4-(4-hydroxyphenyl)-butyric acid.

D-Tyr', in [Metjenkephalin results in a biologically inactive compound withnegligible receptor affinity (112,173). Replacement of the Tyr para-hydroxy group by a p-amino (66), chloro (67), or iodo (68), or substitutionof Tyr' by DOPA (69) results in a loss of agonist activity (Table 11-10)(159). The stringent structural constraints on Tyrt are demonstrated by thehomo (71) and nor (70) tyrosine derivatives, which possess, at most, 4% ofthe GPI/MVD activity of their parent (112,113). The tyrosine has alsobeen replaced by other amino acids and, as shown in Table 11-10, none ofthese has demonstrable activity (159).

Several rigid analogs that constrain tyrosine in a fixed conformation havebeen prepared. One of the most interesting approaches has been to useboth enantiomers of the benzomorphan metazocine in place of tyrosine in[Met]enkephalinamide (175). Both diastereomers of derivatives 76 and 77were prepared to test the hypothesis that the tyramine moiety in rigidopiates and opioids serves an identical functional role at the receptorsurface. It was found that both 76 and 77 were either inactive or feeblyactive in the GP] and MVD assays. This may not have been too surprisinggiven the known lack of activity in N ,N-disubstituted tyrosine enkephalins(163). The conclusion reached was that the rigid opiates and opioidsinteract with the same receptor, but with different modes of binding (175).Another approach has been to constrain the tyramine moiety in an indane,

8, Tyrosine' Structure-Activity Relationships

Of the five amino acid residues in the enkephalins, the structural andconfigurational requirements at tyrosine are the most stringent. Deletionof the Tyrt residue in both [LeuJ- and [MetJenkephalin abolishes biologicalactivity (113,159,172). Likewise, replacement of Tyrt by its enantiomer,

488 II Enkephalins

Table 11.11

Glycine! Substitutions

Tyr-X-Gly-Phe-Y

Compound X Y GP[ MVD References

I Gly Met 1.0 1.083 Ala Leu 0.026" 0.009 11284 o*Ala Leu 1.8-5.5 8.3-9.4 110,112,113,11485 D-Ala Met 1.14-6.3 5.0-7.2 11/ ,1/2,113,/7286 fJ-A[a Leu 0.002 11387 Aib Leu 0.13 11388 Aib Leu-NHz 17889 Aib Met-NH2 /7890 f:-Ahx Leu Inactive Inactive /7991 D-Leu Leu 1.34" 0.020 112,11392 o-Lys Leu 0.18" /8093 D-Met Leu 8.0, 63.<t' 3.0a 113,/6594 D-Met Leu-NH2 4.8,27.5 0.44,3.7 114,/45,16595 D-Met Met-NHz 9.0 0.54 /4596 D-Phc Leu 0.54 /5997 Pro Leu 0.0003 11298 D-Pro Met 0.01 /6/99 D-Ser Met [4.3" 29.5a /65

100 v-Ser D-Leu 1.4 [5 7/101 o-Trp Leu O.06Q 0.05 112,113102 v-Thr Met 0.56 /59Ib3 D-Val Met 0.42 /59

Q Methyl ester.

VI Structure-Activity Relationships in the Enkephalins

CH,II -

T yr-CO- NII-C-CO-G Iy-Phe- Leu104 (i>-Ala'-[Leu]enk)

Tyr-( R)Gly-Gly- Phe-Leu106 (R ~ CH,CO,H)107 (R ~ CH,CH,OIl)

489

Tyr-Sar-Gly-Phe-Leu105

Tyr-( Gly-Gly- Phe. Leu h108

Tyr.CO-NH-CH,-CS-Gly-Phe- Leu109

(184). While compound 106 has virtually no aClivity, the alcohol derivative(107) has 0.43 limes Ihe aClivily of [MetJenk (I) in the MVD assay and only0.06 times in Ihe GPI assay. This hydroxy ethyl side chain may bemimicking the known O-selective effects of Ser and Thr2 (143,144). Adimeric form (108) of [LeuJenk, sharing a common Tyr', has also beenprepared that also shows MVD selectivity but has only weak polency(184). The thiocarbonyl group has replaced the carbonyl group in Gly2 asanother form of conformational constraint. The thioamide analog (109)has 2.6 and 9, I times the activity of [LeuJenk (2) in the GPI and MVDtests, respectively (185),

Various approaches to rigid analogs have been described that incorpo-rate rigid amino acids in place of Gly2 or ring formation between Tyrt andGly2, Methylene bridging of the a-carbon of Gly2 and the nitrogen of Gly2

results in a series of bridged analogs (1l0-1l2), Of these, III has 0.1 times

(ICH2Int

Tyr-NH~N-CH2CO-Phe-Met-NH2

o110

III

112

Among the many approaches to conformation rigidity, the use ofdehydroamino acids has been recently introduced mainly because of theSp2 character of the a carbon. The synthesis of these molecules has beenreviewed (181), Although the Z-isomers are readily available, the syn-thesis of the less accessible E-isomers has been described (182), The useof tl-Ala2 (104) in place of Gly2 has been studied using opiate receptoraffinities with DADLE (33) and dihydromorphine as a ligand. In thesebiochemical assays, 104 is about equipotent to DADLE in displacingdihydromorphine and two-thirds as active as DADLE in displacing itself(183). Consequently, 104 is about one-half as selective as DADLE for the5 receptor. A more classical approach is the alkylation of the peptide chainbackbone, in this case, replacement of Gly2 with sarcosine (Sar), N-methylglycine, The Sar2-analog (105), however, possesses only 1% or lessof the biological activity of [Met]enk (I) (112), An interesting approach isthe N-substitution of Gly' with acetic acid or {3-hydroxyethyl (107) residues

(n:: 2)

(n c 3)

(n:::: 4)

r-\Tyr-N N-CH2CO-Phe-Leu

L../114

113

Table 11-12

Tahle 11-13Gly] Substitutions

Phe4 SubstitutionsTyr-Gly-X-Phc- Y

Tyr-Gly-Gly-X- YCompound X Y GPI MVD References

ReferencesCompound X Y GPI MVDI Gly Met 1.0 1.0117 Ala Leu 0.025 112 I Phe Met 1.0 1.0118 Ala Met <0.01 /59 126 Gly Met Inactive 159119 D-Ala Leu O.OIR 0.0031 1/2.1/3 127 Ala Met Inactive 150120 I)-Ala Met O.t14 O.()()1 1/2./73,/74 128 D-Ala Met <0.01 /59121 I3-Ala Leu <0.001 1/3 129 D-Phe Met <0.01 <0.001 159.173122 Pro Leu <0.001 JJ2 130 Tyt Leu 0.02 1/2123 D-Pro Leu 0.(XJ5 Il2 131 Tyr Met 0.001 /62124 SCT Leu 192 132 Trp Met 0.27 194

490 II Enkephalins VI Structure-Activity Relationships in the Enkcphalins 491

the potency of [Met]enk (1), the others less than 0.01 times the potency(/86,187). The thiazolidinone derivative (113), an analog of a cyclicmethionine, has only 3% of the activity of (Metjenk (1) (/86). The amidenitrogens of Gly2 and Gly3 have also been bridged by an ethylene group(114), resulting in a biologically inactive molecule (/88). Similar resultswere observed with [Metjenkephalin derivatives (189). Formation of animidazolidinone ring between the Tyrl and Gly2 nitrogen (115) results in adrastic reduction of biological activity (190). Similarly, the diketopipera-zine derivative (116) is inactive due to, among other things, the blockade ofthe Tyrl amino group (191). On the whole, the experience with the use ofrigid analogs at Gly2 has been disappointing.

0.3% of [MetJenk (1) (112). Replacement of the Gly3 amide bond in[LeuJenk (2) with a thioamide, similarly to that illustrated in 109, retainsGP! equivalency to [LeuJenk (2), but MVD activity is reduced by 85%(/85). Another rigid analog (125), where the Gly2 and Gly3 amidenitrogens are linked by an ethylene bridge, is also inactive (189).

1\Tyr-D-Ala-N N-Phe-Leu-NH2,

o

D. Glycine3 Structure-Activity Relationships

In terms of the overall enkephalin molecule, Gly3 is a critical section thatallows very little manipulation. Deletion of Gly3 (or, equivalently, GlyZ)drastically reduces GPI activity to less than 0.2% of that of [Met]enkepha-lin (193). Introduction of other natural amino acids also strongly decreasesbiological activity (Table 11-12). Surprisingly, the incorporation of D-Ala3119 and 120, so successful at Gly2, also reduces both GPI and MVDactivity to 2% or less. The replacement of Gly' by Ser3 and dehydroalaninehas been investigated biochemically (/92). With both D- and L-amino acidsso ineffective, it was not surprising that the l3-alanine derivative (121) wasalso inactive, as was Aib' (179).

Backbone methylation, replacement of Gly3 with Sar3 in [LeuJenk (2) incommon with the preceeding observations, also reduces MVD to only

125

In summary, structure-activity relationship studies for Gly3 have indi-cated that all modifications introduced thus far, with the exception of athioamide group. reduce, usually drastically, the biological activity.

E. Phenylalanine4 Structure-Activity Relationships

The Phe4 position of the enkephalins, like the others, has been exten-sively investigated, not only from the structure-activity relationship angle,but also for the determination of receptor type selectivities. Also, incontrast to Tyrl, a significant amount of effort has gone into studying theeffects of substituents on the aromatic ring of phenylalanine. However,similarly to Tyrl, replacement of Phe4 by D-Phe4 (129) effectively abolishesbiological activity (Table 11-13).

Replacement of Phe4 with a variety of other amino acids (Table 11-13),with the ~xception of Trp, eliminates both MVD and GPI activity.

Table 11-16

Phe4 Aromatic Subst;tuents

Tyr-D-Ala-Gly-Phe-(Me )Met-NH,

Phe4 Aromatic AnalgesiaCompound Substitution MVD Mouse Jump (sc) Reference

138 (Metkephamid) H 1.0 0.36 mpk 200139 m-CI 17.2 0.11 200140 m-Br 24.9 0.36 200141 m-CF) 6.9 0.33 200142 m-CH) 4.5 0.33 200143 m-OCH) 4.2 0.15 200144 p-F 15.8 0.02 201

:]I 145 p-CI 5.5 0.67 201146 D-p-CI 0.07 >30 201147 p-Br 5.5 1.6 201148 p-! 0.9 >30 201149 p-CF, 8.1 0.43 201150 p-N02 19.1 0.16 201151 poOH 0.03 >10 201

492 11 Enkephalins

Table 11-14

j,Z.Phe4 Substitutions

Tyr- X -Gly-j, Z

-Phe-Leu

Opiate BindingAnalgesia

Mouse Tail Flick(iv)Compound

DHM(nm)

DADLE(nm)

3.81.9

> 50 mpk130.5

x

133134Morphine

GlyD-Ala

216.4

However, the amino acids investigated do not have the large lipophilic sidecham necessary to replace the aromatic ring of phenylalanine in J.<-selectiveligands (Section IV). Exchange of Phe4 for a'-Phe provides analogs 133and 134, (Table 11-14), which possess high affinity for the opiate receptor;also 133 has hIgher selectIvIty for the 8 receptor (/83). More importantly,the dehydro analogs possess in vivo analgesic properties, although they areweak (/95). However, the [a'-Phe4,Met5]enkephalin amide derivativehas 0.2 times the activity of morphine by intravenous (iv) administration(/95,196). The preparation of E-dehydrophenylalanine has been reported,but has not yet been incorporated into peptides (/82). Another conforma-tionally restricted Phe4 analog is the cyclopropyl derivative (135) (/97).However, both enantiomers are several orders of magnitude less activethan the parent in both the GPI and MVD assays (/97).

~C6H5

Tyr-D-Ala-NH CO-Leu

135

Substitution patterns on the aromatic ring of Phe4 have been investi-gated. The initial results were based on the p-nitro derivatives (Table11-15). Introducing a para-nitro group on Phe4 (136-138) and varying thefifth reSIdue furnIShed analogs with substantially increased GPI and MVDpotencies relative to the unsubstituted [Leu)enkephalin (2) (/98,199).However, smce 2 IS substantially less active in the GPI assay, the Metanalog (138) is 8 selective, while D-Leu (137) does not discriminate.

VI Structure-Activity Relationships in the Enkephalins 493

Table 11-15

Phe4 Aromatic Nitro Substitions

Tyr-D-Ala-Gly-(p-NO,)Phe-X

Compound x GP!" MVD" Reference

136137138

10.551

198199199

22.717435

a Relative to [Leu]enkephalin (2) = 1.

An extensive structure-activity relationship investigation has been con-ducted in meta- and para-substituents on the analgesic peptide, metkepha-mid (138). The results reported for MVD potency and analgesia in Table11-16 are all related to this peptide. In the meta-substitution series, anelectronegative halogen (139, 140) appears to be the best substitution.Other larger electronegative groups such as trifluoromethyl (141) are lessefficient, as are electron-releasing groups (142, 143) (200). Analgesicpotency by sc administration parallels the MVD potencies but is not assensitive. Para-substitutions show a generally similar pattern to the meta,with electron-withdrawing groups yielding the most potent peptides:Fluorine (144) and nitro (ISO) have similar MVD potencies, with (144)

1..


VI Structure-Activity Relationships in the Enkephalins494 11 Enkcphalins

Tyr-D-Met-Gly-Phc( 611 )-X

N-Alkylatcd LPhe4]-Tetrapeptide Amides

RTyr-D-Ala-Gly.L Phe-NH2

Hexahydrophenylalamine Derivatives

495

Compound GP["Analgesia

x

152153

Met-NH2Leu-NH2 Compound

3.02.3

0.310.10

"Relative to [MetJenkephalin (I) = 1. 154155156157158159160161162163164165

being approximately eight times more analgesic (201). The D-p-chloroderivative (146) is substantially less active than the L-p-chloro derivative(145). The electron-releasing and acidic p-hydroxy group, replacement ofPhe4 with Tyr4, is even less active than the D-p-chloro (146) in the MVDassay and has very weak analgesic properties (201). Similar results havebeen reported for the tetrapeptides, lacking the fifth amino acid, relatedto (138) (202).

The aromatic ring of Phe4 is not necessary for biological activity.Reduction to the hexahydro derivative can furnish analgesic enkephalins,which were origina)ly thought to lack physical dependency (203), althoughthis was later disproved (204). Incorporation of Phe(6H)4 in the [D-Met2]enkephalamides 152 and 153 (Table 11-17) yields peptides that areslightly more potent in the GPI test and substantially less active in theMVD assay (145).

The effect on GPI and MVD activity on replacement of Phe4 by largealkyl groups has been discussed in Sections IV and V.

Backbone alkylation of Phe4 has been used extensively, primarily withthe introduction of methyl and ethyl residues. A thorough investigation hasbeen reported in a tetrapeptide where the alkyl group has been variedsystematically among both alkyl chains and those groups known to impartantagonist and mixed agonist-antagonist properties in classical rigidopiates (Table 11-18) (205). For MVD activity, potency peaks at N-ethyl(156) for the alkyl substituents, being almost 90 times more potent than theunsubstituted parent (154). Substantial MVD activity is also shown by theopiate antagonist, mixed agonist-antagonist substituents (159-161).Analgesic efficacy is also achieved by alkylation of the Phe4 amidenitrogen, with the N-ethyl analog (156) being some 280 times more potentthan the un substituted parent (154) and 150 times more potent than itsN-melhyl congener (155). Analgesic potency diminishes with the largerhpophilic substituents (158), as well as with the shorter, more hydrophilicdenvalIves (163, 164) (202,205). Whether the derivatives 159-161 possessopiate antagonist properties was not disclosed.

R

IICH3C2H5fI-C.~H7fI-C"HI1CII,CII~CII,CHrc-C3H5CII,C![~C(CII,),(CII,),SCII,CII,CO,CH,CII,CH,OIlCH2CII2F

MVD" Mouse Hot Plate (st:)

0.110.179.51.80.072.4

12.33.14.7

0.100.400.52

O.ssmpk0.470.0030.15

11.70.010.0120.40.051.40.330.013

"Relative to (Met)enkephalin (I) = I (reference 225).

The thioamide grouping has been introduced at Phe4 to generateconformationally restrained enkephalin analogs. The [Leu]enkephalinderivative containing the thioamide in place of the amide group at Phe4 is,however, equipotent to [Leu]enkephalin in both the MVD and GPI assays,as well as in IL and 8 opiate receptor affinities (185). A rigid analog wasprepared by joining the Phe4 amide nitrogen to the Leus amide nitrogen bya 2-carbon bridge (189). The diastereomers of the resultant (166) were

166

separated, and neither had appreciable binding for the opiate receptor andonly weak analgesic properties.

In summary, the Phe4 position has considerable latitude in terms of whatsubstitutions can be accommodated without drastic decreases in biologicalactivity. The phenylalanine aromatic ring can be substituted or reduced,

Table 11-19

Introduction of D-Lcu5fMet5 and the Effects of Me,s Oxidation

Tyr.X-Gly-Phe-Y

Compound X Y GPt MVD References

2 Gly Leu 0.36 1.2 /12 CI167 Gly f)-Leu 0.15 1.4 /12,15984 D-Ala Leu 5.5 9.0 /1833 o.Ala D-Leu 3.3 27 /18

I Gly Me' 1.0 1.0 /18168 Gly o-Met 0.1t 0.002 /59./7385 D-Ala Met 5.6 5.0 /18

169 D-Ala o-Mct 1.8 5.9 /18170 Gly Met(O) 0.2 0.67 /64171 Gly Met(O,) 0.01 /59172 D-Ala Me'(O)-NH, 206

.6.J

496 11 Enkephalins VI Structure-Activity Relationships in the Enkephalins 497

the amide nitrogen can be alkylated, and Phe' can be replaced with otheraromatic amino acids such as Trp4.

of the activity of their corresponding parents, respectively (Il3,207).Replacement of Met'/Leu' with hydrophilic groups, such as hydroxyalkylamides (25) (DAGO) or aminoalkylamides 175 and 176, leads to asignificant enhancement of GPI effects and a decrease in MVD activity(134). These compounds, 175 and 176, are potent analgesics by ivadministration. A similar but much stronger effect is observed with 177,which contains a highly lipophilic group. In 177, the GPI potency is 92times that of [Met]enkephalin (I), while it is only 0.5 times as potent in theMVD assay (208) Reduction of both I and 2 to their correspondingalcohols 178 and 179, retains both receptor affinity and GPI activity(Il2,13i). The corresponding [D-Ala2,Met'-01] derivative (180) and itscorresponding sulfoxide both possess strong opiate receptor affinity andare potent analgesics by parenteral administration (135). The reductIOn ofthe terminal amino acid to the corresponding alcohol has served to preparebiologically potent enkephalin derivaties, for example, (24-26).

Tyr.Gly.Gly.Phe.R173 (R = NH(CH,),SCH,)

174 (R = NH(CH,),CH(CH,),)

F. Methionine'/Leucine' Structure-Activity Relationships

Structural and conformational changes at the Met'/Leu' position arewell tolerated and have led, almost invariably, to active compounds. Thetetrapeptide, Try-Gly-Gly-Phe, resulting from removal of the terminalamino acid, retains activity in both the GPI and MVD assays(Il2,Il3,159). Similar but more potent biological activity was observedwith the D-Ala2 tetrapeptides reported in Table 11-18. Replacement ofLeu' by its optical antipode, D-Leu' (167), results in a decrease in GPIpotency, while the MVD activity is unchanged (Table 11-19). A similardecrease is observed with DADLE (33), but the MVD is increasedthreefold. In [Met]enkephalin (I), replacement with D-Met' (168) signi-ficantly decreases GPI activity and virtually eliminates MVD. With D-Ala2,the use of D-Met' (169) yields a peptide qualitatively similar to [D-Leu']enkephalin (167), where activity is reduced and MVD unchanged.Oxidation of the sulfide of methionine in I to the sulfoxide results in agreater decrease in GPI than MVD potency, but the compound (170) stillretains significant. activity in both assays. Sulfone formation (171) de-creases GPI activity IOO-fold. The D-Ala2 sulfoxide (172) has beenreported to be 30-50 times more potent as an analgesic than the corres-ponding methionine derivative (206).

Decarboxylation of [Met]- and [Leu]enkephalin I and 2 yields thetetrapeptide amides 173 and 174, which retain 7% (MVD) and 0.6% (GPI)

Tyr-o-Ala-Gly-McPhc-R175 (R = NII(CH,),N(CH,),)176 (R = NH(CII,),NO(CH,),)

Tyr-D.Ala.G Iy.Phe-N.( CH,) ,GI( CH ,),I

CH2Ct,lls177

Tyr-Gly-Gly.Phe-R178 (R = Met'DI)179 (R = Leu-ol)

Tyr-D-Ala-Gly-Phc-Mct-ol180

Tyr-Gly-Gly- Phe-NH( CH, J,CO,H

189

Tyr-Gly-Gly-Phe-R190 (NH-CH(CH,CH(CII,),)PO,H,)191 (NH.CH(CH,CH,SCII,)pO,H,)

Replacement of Met'/Leu' with a variety of other naturally occurringamino acids leads to a significant reduction in biological activity, with theexpected exceptions of isoleucine (184) and norleucine (185) (Table11-20). The use of 6-aminohexanoic acid in position 5 (189) was unsuccess-ful, but the [D-Met2] analog of 189 was very potent, equivalent to 0.75 times

408 II Enkephalins

Table 11-20

Met~/Lcu'" Substitutions

Tyr-Gly-Gly-Phc-X

Compound X GPI MVD References

I Met 1.0 1.0 1/8181 Ala 0.029 o.lm 1/2.1/3182 D-Ala 0.065 1/3183 Gly 0.02 0.03 162184 lie 0.78 159185 Nle 0.5 2U9186 Phe 0.11 /59187 Pro 0.IX15 IWll 159188 Val 0.04 1/2

the potency of morphine parenterally (179). The synthesis of a wide varietyof amino acids in which the carboxyl group has been replaced by aphosphonic acid and the incorporation of these acids as the fifth residue inenkephalin have been reported (2/0). The Leus/MetS analogs 190 and 191possess analgesic properties (2/1). The carboxyl group of DADLE (33)has been converted into a chloromethyl ketone (192) in an attempt toprepare an irreversible receptor ligand (212). This ligand, DALECK(192), binds irreversibly to the high-affinity opiate-binding site and inducesa long-lasting, dose-dependent analgesia (212). Leu' has also been con-verted to the dehydroamino acid and incorporated into the analogs 193and 194 in order to retard enzymatic hydrolysis of the amide bond.

CII,CH(CHd,I - -

Tyr-o-Ala.Gly-Phc-l'tl-Ctl.COCI t,Cl192

Tyr-Gly-Gly- Phe-.l z. Leu

193

Tyr-o-Ala-Gly- Phe-.l". Leu194

Tyr-D-Ala-Gly-Phe-Nt t.CH((G I, ),SCt t dCSNI t(CH,)

195

1\Tyr-Gly-Gly-Phe-N NH

HR 0

196 (R = CII,CH(CII,J,I197 (R = (CH,I,SCH,)

VI Structure-Activity Relationships in the Enkcphalins 499

Both peptides possess affinity for both the J.Land I>opiate receptors and areapproximately equivalent to [Leu]enkephalin (2). As analgesics, 194 has2% of the iv activity of morphine, while 193 is inactive (183,213).

The N-backbone methylation of [Leu]enkephalin (2) and its o-Ala2analog (84) does not result in any significant change in either in vitropotency or selectivity (159,169). However, the increased resistance tohydrolytic enzymes by this N-methyl substituent can substantially increaseanalgesic potency in enkephalin-based analgesics. The thioamide groupinghas also been used to provide enzyme resistance and conformationalrestraints. For instance, the thioamide (195) possesses substantial analgesicpotency by icv administration and is reported to have a better therapeuticindex than [Met]enkephalin (I) (214). Rigid analogs, in which either Met'or Leu5 amides are constrained in a six-membered ring, have beensynthesized (189). The rigid analog (196) of [Leu]enkephalin (2) is 4.5times as potent iv as morphine in the tail flick test. The methionine analog(197), while possessing greater affinity for the opiate receptor, approxi-mates morphine as an analgesic (189).

G. The Enkephalin C- Terminus

The effect of C-terminal amidation on biological activity has beenillustrated in Table 11-3. The N-ethylamide of [o-Ala2,Pro5]enkephalindisplays similar GPIIMVD properties and is approximately equivalent inpotency to the parent amide (165). A series of N-alkyl amides of[o-Ala2,Met5]enkephalin showed GPI potency peaking at ethyl and icv hotplate analgesia peaking at n-propyl (2.1 times that of morphine) (215). Theincrease in chain length to six amino acids by addition of the Thr" (35) orSerb (34) to yield highly I>-specific peptides has also been mentioned

(71.143,144),

I

I

~

H. EnkephaIin-Based Opioid Antagonists

The N-substituents necessary for inducing opiate antagonist propertiesinto the rigid opiates have been well characterized in the precedingchapters. The introduction of these substituents, cyclopropylmethyl orallyl, to the N-terminus of enkephalins has led, in the monosubstitutedcases, either to agonists with sharply reduced biological activity or, at best,to partial agonists (111,208,216,217). On the other hand, the N,N-diallylcompound (198), and its more stable isosteric analog (199), where theGly3_Phe4 bond has been replaced by CHz-S-, are pure antagonists with I>

opiate receptor selectivity (218,219). Antagonists 198 and 199 possess a IO-ta 3D-fold selectivity in antagonizing [Leu ]enkephalin (2) over normor-phine in MVD preparations. Structure-activity investigations primarily

\00 11 En kephalins

N.N-( Allyl h Tyr-Gly-Gly- Phc- Leu

198

N.N-(Allylh Tyr-Gly-NH(CH,hS-CH(CH,C,H,)CO-Leu199

N. N-(Allylh Tyr- Aib-Aib- Phe- Leu

200

Tyr-D-Ala-Gly-MePhe-N( CH ,) (CH,hC,H,201

involving the second and fifth enkephalin residues led, in most cases, tocongeners with lower affinity and selectivity (220). What came out of thisinvestigation was that structure-activity relationship data developed forthe agonist enkephalins were not transferable to an antagonist series_ Ahighly selective 8 receptor antagonist has been developed by replacing thetwo glycine residues in 198 with two Aib residues (200) (221). The selective8 antagonist (200) is equipotent with naloxone at that receptor, but isdevoid of activity at the /J.and K receptors below a concentration of 5 /J.m.

A different approach to antagonists is based on the secondary ami des ofa tetrapeptide_ The prototypic peptide is 201, which is a pure antagonist inthe MVD with a iO-fold selectivity for the /J.receptor. An initial structure-activity relationship study did not result in improved affinity or a dramaticchange in receptor selectivity. However, both the Phe4 methyl group andthe secondary amide are critical for antagonist properties; for example, thestructurally similar analog (177) is a pure agonist (208).

VII. Clinically Investigated Enkephalin Analgesics

Despite the literally thousands of peptides synthesized and tested asanalgesics, only three have been investigated clinically: metkephamid,LY-127,623 (222); FK33-824 (DAMME) (223); and [D-Met2,Pro'].en kephalin amide (224). All of the peptides contain a selection of modifi-cations inserted to retard enzymatic hydrolysis: D-amino acids, backbonemethylation, or reduction of a carboxyl group to the alcohol.

Metkephamid (202) was reported in 198] by the group at Lilly (225).The peptide (202) is slightly more 8 selective (1.7 times) than [Met]en-kephalin in the MVD assay. By icv administration, metkephamid was atleast 100 times more potent than morphine. By sc administration, it wasmore potent than morphjne, meperidine, pentazocine, or codeine in thewrithing and mouse hot plate jump assays. In the mouse hot plate paw lickand rat tail flick assays, 202 has about one-third the potency of morphine.

VII Clinically Investigated Enkephalin Analgesics \01

Tyr-D-Ala-Gly-Phe- MeMet-NHz202 (melkephamid. LY-127.623)

Tyr-o-Ala-Gly-MePhe-Mct( 0 )-01

26 (FK 33-824). DAMME)

Tyr-D-Mct-Gly-Phe- Pro-NHz

203 ([D-Met2,ProS]enkephalinamide)

By iv administration, it has somewhat less analgesic potency than by scadministration. The duration of metkephamid-induced analgesia was in-termediate between that of meperidine and morphine. A physical depen-dence study indicated that 202 produced only slightly more dependence inrats than saline_ Metkephamid has minimal effects on respiration, with noeffects being noted below 64 mpk (225,226). Clinically, metkephamid wasadministered to postoperative patients and had an onset of action of 0.5hour and a duration of about 4 hours. Side effects were noted in 80% of thepatients. Besides the usual opiate side effects, actions unique to metkepha-mid were a feeling of heaviness in the limbs, emotional dissociation, aburning sensation at the injection site, dry mouth, and nasal congestion. Itwas suggested that some of these effects might be due to 8 receptor activity(226,227). It was stated that the side effects were not overly distressing(227).

FK 33-8214 (26) was reported in 1977 by the group at Sandoz (135). Anumber of in vivo studies have demonstrated that it is a potent analgesic.On icv administration, FK 33-824 is 1000 times more potent than morphinein the mouse tail flick assay_ The peptide was twice as active as morphineon sc administration and orally had 0.2 and 0.3 times the activity ofmorphine in the tail flick and hot plate assays, respectively. The &nalgesiawas dose dependent and naloxone reversible. Tolerance and physicaldependence have been produced in monkeys, and withdrawal symptomswere observed after rapid drug withdrawal (135). While respiratorydepression is apparent with 26, its therapeutic index, related to analgesia,appears to be large (228).

In humans, FK 33-824 has been tested for potential therapeutic effective-ness in schizophrenia (229). The peptide also releases prolactin (230) andinhibits luteinizing hormone secretion (231)_ When administered, FK 33-824 demonstrated many of the same symptoms as metkephamid (202):Heaviness of the limbs and muscles, often coupled with a feeling ofoppression on the chest or a tightness in the throat (232,233), facialflushing, and dry mouth were observed (232). Other commonly observedmorphine-like effects were noticeably absent. As an analgesic in humanswith postoperative pain, its efficacy was less than that of morphine, and the

1

102 II Enkephalins References 103

analgesia was unpredictable and insufficient, and with a shorter durationthan morphine in at least half of the patients (234,235),

The third clinically investigated enkephalin derivative is [D-Met2,Pro'J-enkephalinamide (203), which was reported in 1977 by a Hungarian group(236,237), As an analgesic, by icv administration, 203 was 70 times morepotent than morphine in the tail flick and hot plate tests, By iv injection,it was about three times more potent tban morphine. The effects werenaloxone reversible. Typical morphine-like side effects were noted in therodents, Tolerance to the analgesia developed more rapidly in rats thanwith morphine (238). When administered to healthy human volunteers,the usual autonomic side effects were observed (heaviness in the limbs,dry mouth, etc.). Emotional detachment was again noted. As with 26,prolactin was released. An elevation in the pain threshold was reported(239),

VIII. The Chemical Anatomy of the Enkephalins

6. The fifth position also tolerates a great deal of manipulation, withmost changes resulting in active compounds. Oxidation of Met' to itssulfoxide, but not its sulfone, results in enhanced analgesic prop-erties. Both Leu5/Met5 can be de carboxylated as well as replaced byother natural and unnatural lipophilic amino acids. Reduction of thecarboxyl group to the alcohol results in either retained or enhancedanalgesic potency. Formation of amides usually results in enhancedstability.

7. Amide backbone substitution at Phe4 and Met'/Leu' can producepotent analgesics, but introduction at either Gly2 or Gly3 is con-traindicated.

The functional group dispositions that influence J.Land 8 opiate receptorspecificities are:For J.Lreceptor specificity:

1. Decreasing the number of amino acids in the peptide.2. Introduction of a lipophilic D-amino acid at Gly2,3. Replacement of Phe4 by a large lipophilic chain.4. Hydrophobic amino acids at position 5.5. A folded conformation.

For /5 receptor specificity:

1. The presence of the aromatic ring of Phe42. A hydrophilic C-terminus3. A hydrophilic D-amino acid at Gly2.4. An extended conformation. However, the /5specificity observed with

cyclic penta-en kephalin derivatives may qualify this requirement.

The enkephalins I and 2 and their derivatives represent a special caseamong the opiate-based analgesics in that they are peptides. As such, theyare subject to the action of proteolytic enzymes in addition to the usualmetabolic, transport, tissue distribution, and CNS penetration problemsinherent in the rigid opiates. This and the observation that the majority ofthe published biological data on enkephalins are based on the GPI andMVD assays make structure-activity relationship extrapolations in thisarea more uncertain than usual. Tbat the use of enkephalins for analgesiais a viable approach has been demonstrated by the clinical evaluation ofseveral peptides. With the above reservations in mind, biological activity inthe enkephalins shows the following trends:

1. The minimum chain length for analgesia is the first two amino acidswith a lipophilic amide side chain.

2. A functioning amino group, eitber unsubstituted or monosubstituted,on tyrosine is necessary, as is the phenolic hydroxyl. Most otberchanges result in drastic reductions in activity.

3. Substitution of D-amino acids for Gly2 usually increases activity,whereas L-amjno acid substitution, decreases it.

4. Little change is tolerated at Gly35. Phe4 tolerates a great deal of change. The aromatic ring can be

reduced or substituted for by electron-withdrawing groups. A de by-drophenylalanine derivative possesses analgesic properties. Phe4 canbe substituted for by Trp but not by most other amino acids,

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200. P. D. Gcscllchen and R. T. Shuman, U. S. Patent 4,322,339, March 30, 1982..201. P. D. Gcscllchen, R. C. A. Frederickson, S. Tafur, and D. Smiley, in "Pepttdes.

Proceedings of the 7th American Peptide Symposium" (D. H. Rich and E. Gross, eds.),p. 621. Pierce Chemical Co., Rockford, Illinois, 1981.

202. R. T. Shuman and P. D. Gesellchen, U. S. Patent 4,322,340, March 30, 1982.203. B. Filippi, P. Giusti, L. Gma, G. Borin. F. Ricchelli, and F. Marchiori, Int. J. Pept.

Protein Res. 14, 34 (1979).204. J. S. Morley and E. T. Wei, Int. J. Pept. Protein Res. 16, 254 (1980).

.205. R. T. Shuman, P. D. Gesellchen, E. L. Smithwick, and R. C. A. Fredenckson, in"Peptides, Procceedings of the 7th American Peptide Symposium" (D. H. Rich andE. Gross, cds.), p. 617. Pierce Chemical Co., Rockford, Illinois, 1981.

206. J. A. Kiritsy-Roy, S. K. Chan, and E. T. Iwamoto, Ufe Sci. 32, 889 (1983).

207. R. C. A. Frederickson, R. Nickander, E. L. Smithwick, R. Shuman, and F. H. Norris,in "Opiates and Endogeous Opioid Peptides" (H. W. Kosterlitz, ed.), p. 239. North-Holland Pub!., Amsterdam, 1976.

208. J. D. Bower, B. K. Handa, A. C. Lane, B. A. Morgan, M. J. Rance, C. F. C. Smith,and A. N. A. Wilson, in "Peptides, Proceedings of the 7th American Peptide Sympo-sium" (D. H. Rich and E. Gross, eds.), p. 607. Pierce Chemical Co., Rockford, Illinois,1981.

209. S. Bajusz, A. Z. R6nai, J. 1. Szekely, Z. Dunai-Kovacs, I. Berzctei, and L. Graf, ActaBiochem. Biophys. Acad. Sci. Hung. II, 305 (1976).

210. L. Kupczyk-Subotkowska and P. Mastalerz, Int. J. Pept. Protein Res. 21,485 (1983).211. P. Mastalerz, L. Kupczyk.Subotkowska, Z. S. Herman, and G. Laskawiec, Naturwis-

senschaften 69, 46 (1982).212. M. Szucs, S. Benyhe, A. Borsodi, M. Wollemann, G. Jancs6, J. Szecsi, and

K. Medzihradszky, Ufe Sci. 32, 2777 (1983); M. Szucs, Drugs Future 9, 416 (1984).213. Y. Shimohigashi and C. H. Stammer, J. Chern. Soc., Perkin Trans. I p. 803 (1983).214. K. Rolka, M. Kruszynski, and G. Kupryszewski, Acta Pharm. Suec. 21, 173 (1984).215. R. B. Mathur, B. J. Dhotre, R. Raghubir, G. K. Patnaik, and B. N. Dhawan, LifeSci.

25, 2023 (1979).216. C. B. Pert, D. L. Bowie, A. Pert, J. L. Morell, and E. Gross, Nature (London) 269, 73

(1977).217. E. F. Hahn, J. Fishman, Y. Shiwaku, F. F. Foldes, H. Nagashima, and D. Duncalf,

Res. Cornmun. Chern. Pathol. Pharmacal. 18, 1 (1977).218. J. S. Shaw, L. Miller, M. J. Turnbull, J. J. Gormley, and J. S. Morley, Ufe Sci. 31,

1259 (1982).219. J. J. Gormley, J. S. Morley, T. Priestly, J. S. Shaw, M. J. Turnbull, and H. Wheeler,

Life Sci. 31, 1263 (1982).220. P. Bclton, R. Cotton. M. B. Giles, J. J. Gormley, L. Miller, J. S. Shaw, D. Timms, and

A. Wilkinson, Ufe Sci. 33, Supp!. 1, 443 (1983).221. R. Cotton, M. G. Giles, L. Miller, J. S. Shaw, and D. Timms, Eur. J. Pharmacol. 97,

331 (1984).222. W. Werner and M. Puig, Drugs Future, 5, 81 (1980); update: 7, 129 (1982).223. M. Puig, Drugs Future 3,511 (1978); updates: 4, 529 (1979); 5, 368 (1980); 6, 443 (1981);

7, 523 (1982); 8, 648 (1983); 9, 548 (1984).224. D. M. Paton. Deugs FUMe, 4, 711 (1979); updates: 6, 648 (1981); 8, 897 (1983).225. R. C. A. Frederickson, E. L. Smithwick, R. Shumam, and K. G. Bemis, Science 211,

603 (1981).226. R. C. A. Frederickson, E. L Smithwick, and D. P. Henry, Int. Brain Res. Organ.

Manage. See. 7, 227 (1980).227. J. F. Calimlim, W. M. Wardell, K. Sriwatanakul, L. Lasagna, and C. Cox, Lancet

p. 1374 (1982).228. A. Pazos and J. Fl6rez, Eur. J. Pharmacal. 99, 15 (1984).229. N. Nedapil and E. Ruther, Pharmakopyschiatr. Neuro-Psychopharmakol. 12, 277

(1979).230. J. Brownell, E. del Pozo, and P. Donatsch, Acta Endocrinol. 94, 304 (1980).231. Y. Kato, S. Hirota, H. Katakami, N. Matsushita, A. Shimatsu, and H. Imura, Proc.

Soc. Exp. Bioi. Med. 169, 95 (1982).232. B. von Graffenried, E. del Pozo, J. Roubicek, E. Krebs, W. Poldinger, P. Burmeister,

and L. Kerp, Nature (London) 272, 729 (1978).233. G. Stacher, P. Bauer, H. Steinringer, G. Schmierer, B. Langer, and S. Winklehner,

Gastroenterology. 83, 1057 (1982).

5\2 11 Enkephalins

234. H. B. Andersen, B. C. Jorgensen. and A. Engquist, Acta Anaesthesia/. Scand. 26,69(1982).

235. G. Stacher, P. Bauer, H. Steinringer, E. Schreiber, and G. Schmierer, Pain 7, 759(\979).

236. J. 1. Szekely, A. Z. R6nai, Z. Dunai-Kovacs, E. Miglecz, I. Berzetri, S. Bajusz, andL. Graf, Eur. J. Pharmacal. 43,293 (1977).

237. S. Bajusz, Z. R6nai. J. I. Szekely. L. Graf. Z. Dunaj-Kovacs, and I. Bcrzetei. FEBSLetl. 76, 91 (1977).

238. E. Miglccz, 1. I. Szekely. and Z. Dunai-Kovacs, Psychopharmacology (Berlin) 62, 29(1979).

239. J. Foldes, K. Torok, J. I. Szekely. J. Borvcndeg, I. Karczag. and J. Tolna, Life Sci. 33,Suppl. I, 769 (1983).

12.

Physical Chemistry and Molecular Modelingof the Enkephalins

I. Introduction . . . . . .II. Solid-State Conformations

A. X-Ray Crystallography.. . ......B. Laser Raman, Infrared, and Solid-State NMR Spectroscopy

III. Solution Conformations . . . .A. Studies in Organic SolventsB. Studies in Aqueous Solution

IV. Molecular Modeling Studies.

V. QSAR Studies

References

5\35\4514515516516525532537537

1. Introduction

The enkephalins have numerous degrees of conformational freedom,suggesting Ihat they may exist in many conformalional states. Extensiveeffort has gone into the study of the solid-state, solution, and free-spaceconformations of these compounds, with the expeclation Ihat a low-energyconformation can be identified that is closely related to the "active"conformation. Such a conformation would be useful in relating thestructural features of enkephalins to those of other opiate-type compoundsand could be utilized in the design of new analgesics. Since il is not yetfeasible to determine the conformalions of these compounds while theyare bound to their receptors, conformalional information has been takenfrom crystallographic sludies, spectroscopic investigalions, and conforma-tional energy calculations. Each of these melhods has inherent limitations,and in all cases one may question the relevance to the receptor-sitesitualion. Nevertheless, such studies provide some indication of the rangeof conformations possible, and they often inndicate types of intramolecularand intermolecular interactions that should be considered. Two excellentreviews have been published on conformation-activity relationships in theenkephalin series (1,2).

Conformations of peptides may be described at two levels: the con-formation of the peplide backbone and the rotamers of the side chains.Unless otherwise specified, the following sludies presume the existence oftrans-amide bonds. The conventions used to describe side chain rotamersare illuslrated in Fig. 12-1.

513

\14 12 Physical Chemistry and Molecular Modeling of the Enkephalins

HH-,CxH

-HN~CO-R

{19-1 t I (g+t J III 19-£1")

Fig. 12-1. Conventions used to describe side chain rotamers.

II. Solid-State Conformations

Several X-ray crystallographic studies of enkephalins and some of theiranalogs have appeared. In addition, laser Raman and solid-state nuclearmagnetic resonance (NMR) spectroscopy have been employed In examIn-ing the cooformational behavior of these compounds.

A, X-Ray Crystallography

Smith and Griffin (3) reported the first crystallographic study of[Leu]enkephalin. They found a Tyr-Gly-Gly-Phe j3-bend conformation(type I'J with hydrogen bonds linking the Tyr-C=O to Phe-NH andTyr-NH3 + to Phe-C=O (Fig. 12-2). These workers reported some dIS-order in the tyrosine side chain position, with two apparent conformerspresent. The tyrosine Ca-C~ bond is close to rotamer I of Fig. 12-1, whichis similar to the tyramine conformation observed in the crystal structure ofmorphine (4). However, neither tyrosine conformation observed in[Leu]enkephalin showed a C~-Cy rotation close to that of morphine. Thephenylalanine side chain conformation corresponded to rotamer I, as dIdthe leucine side chain. It was pointed out that the Gly-Gly conformatIOn

+H' NH-,

~6

l.u

Fig. 12-2. Tyr-Gly-Phe ,B-bend conformation.

I II Solid-State Conformations\1\

observed in the crystal structure is sterically not available to L-amino acids,although a D-amino acid in position 2 could be accommodated.

Subsequent to this work, Blundell et al. (5) reported a different spacegroup for this crystal structure in which the tyrosine side chains were notdisordered but exhibited four separate conformations in the unit cell.These four molecules have nearly identical backbone conformations butshow two different tyrosine side chain orientations. The remainder of thestructure is essentially as described by Smith and Griffin.

Karle and co-workers (6,7) examined another crystallographic form of[Leu]enkephalin. The unit cell of this form contains four molecules of[Leu]enkephalin and 40-50 molecules of solvent (water and dimethylfor-mamide). All four molecules have essentially extended backbone con-formations. Some differences were found in the conformations of thetyrosine and leucine side chains. For the tyrosine side chain, two moleculeswere in conformation II and two were in conformation II!. All fourphenylalanine side chains exhibited conformation I. The leucine side chainwas found in rotamer I in three cases and rotamer II in the other.

Japanese workers (8,9) determined the structures of [Metjenkephalin,[4' -Br-Phe4j-[Met]enkephalin, and [4' -Br-Phe4j-[Leu]enkephalin. Theyobserved the latter compound in essentially the same conformation asdescribed by Smith and Griffin (3) for [Leu]enkephalin, with the Tyr-Gly-Gly-Phe j3-bend and two different tyrosine conformations. The [Met]en-kephalin structures could not be solved at high resolution, but low-resolution Patterson maps gave evidence of essentially extended peptidebackbones in both compounds. These workers subsequently determinedthe structure of the tert-butyloxycarbonyl derivative of [4'-Br-Phe4j_[Met]enkephalin (10), a compound that retains some analgesic activity. Inthis case, the backbone was found in an extended conformation. Thetyrosine side chain exhibited conformation I, the phenylalanine side chainconformation II, and the methionine conformation I.

The tetrapeptide fragments Tyr-Gly-Gly-Phe and Gly-Gly-Phe-Leuhave been examined crystallographically (11.12). Tyr-Gly-Gly-Pheadopted a j3-bend structure similar to that found by Smith and Griffin, butGly-Gly-Phe-Leu showed no intramolecular hydrogen bonds.

B. Laser Raman, Infrared, and Solid-State NMRSpectroscopy

Han and co-workers (/3) obtained the laser Raman spectra of[Leu]enkephalin, four different l3C-labeled [Leu]enkephalins, mid sev-eral model compounds. These workers interpreted the spectroscopicresults in terms of the type I' j3-bend reported by Smith and Griffin (3), as

516 12 Physical Chemistry and Molccular Modeling of the Enkephalins

shown in Fig. 12-2. The same group used infrared spectroscopy to showthat [Leu]enkephalin exists as the zwitterion in the solid state (14).

Tyrosine labeled with deuterium at positions 3 and 5 of the aromatic ringwas used by Rice et at. (15) to prepare labeled [Leujenkephalin. Thedeuterium-labeled enkephalin was studied with deuterium NMR in thesolid state in order to derive information about the tyrosine ring motions.The tyrosine ring was found to execute 1800flips around the CwC, bond ata rate of 50,000/sec.

III. Solution Conformations

Numerous and sometimes conflicting reports have appeared in theliterature regarding the solution conformation(s) of enkephalins. Discre-pancies may arise from differences in the methods used, as well as fromvariables such as sample concentratjon, solvent, pH, temperature, ioniza-tion state, and buffers. The majority of studies employed NMR spectros-copy, but ultraviolet, circular dichroism, infrared, and fluorescencemethods have also been used. The following discussion will be divided intotwo parts: first, studies carried out in organic solvents or aqueous-organicmjxed solvents, and second, studies carried out on enkephalins in aqueoussolution. In each of these sections, backbone conformation will beexamined first, followed by side chain conformations.

A. Studies in Organic Solvents

Khaled and co-workers (16) showed that the spectra of enkephalins areconcentration dependent in many organic solvents (dimethylsulfoxide,trifluoroethanol, methanol) using ultraviolet, circular dichroism, protonNMR, and carbon-13 NMR spectroscopy. At low concentration (1 mM),enkephalins are expected to exist in monomeric form, while dimers andhigher associated forms may exist at higher concentrations (100 mM).Khaled et at. interpreted their results in terms of an extended anti parallell3-pleated sheet structure at high concentration (Fig. 12-3). The concentra-tion dependence is a particularly important consideration in NMR studiesbecause NMR tends to be a less sensitive method, and high sampleconcentrations are often used to overcome the limitation in signal sensi-tivity.

The first NMR studies of an enkephalin reported were those of Roquesand co-workers (17-19). They carried out variable-temperature studies on(Met]enkephalin in dimethylsulfoxide. On the basis of coupling constants,conformational energy maps, and the low temperature dependence of the

III Solution Conformations 517

""OH

51I ~ II

""H 0 H 0 R

H,~ NJ~y ~ACO,0'0 H 0 H':, I, i.

'H ° H 0'00,cyNi

b, ~N1f'~ NH,"

1=1 f _H 0H-..;;::

~ /, \ 0HO

Fig. 12-3. Postulated dimeric form of enkephalins.

Mct-NH resonance, they proposed that the peptide exists in a type Il3-bend conformation, as shown in Fig. 12-4. Such a conformation shouldbe stabilized by the Met-NH to Gll-c=o hydrogen bond as well as theinteraction of the charged end groups. The proposed folded conformationwas further supported by the measured 13C spin-lattice relaxation times,which indicated that the internal a-carbons have about the same mobilityas the a-carbons of the terminal groups. Similar results were observedwhen the solvent was a I: I mixture of dimethylsulfoxide and water.

Similarly, Jones et at. (20) found the Met NH proton to have a very lowtemperature dependence in dimethylsulfoxide solution. These workersalso proposed a type I l3-bend conformation, as shown in Fig. 12-4.

In contrast to the above findings, Bleich and co-workers (21) found noevidence for hydrogen bonding from the temperature dependence of theNH protons of [Met]enkephalin in dimethylsulfoxide solution. All amideprotons exhibited temperature coefficients well above the value expectedfor hydrogen-bonded species.

This discrepancy was resolved by Jones et at. (22), who demonstratedthat the findings of Bleich and co-workers correspond to the behavior of

OH

~~"YNl

H'~~QCH~ ~~ ~I '"

''yN~R

0Fig. 12-4. Gly-Gly-Phe-X l3-bend conformation.

1

518 12 Physical Chemistry and Molecular Modeling of the Enkephalins

the cationic form in dimethylsulfoxide solution. while the ,,-bend con-formation is characteristic of the zwitterionic (or neutral) form of[Met jenkephalin.

Han et al. (/4) addressed the question of the ionization state of[Leu]enkephalin in dimethylsulfoxide solution. On the basis of infraredstudies. they concluded that there is a mixture of zwitterionic and neutralspecies in dimethylsulfoxide. From this, they inferred that, in dimethyl-sulfoxide, the carboxylate and amino groups have similar pK, values.

The conformation of [Leu]enkephalin in dimethylsulfoxide solutioninitially appeared to he less well defined. Garbay-Jaureguiberry er al. (23)considered both the type I and type II' ,,-bend conformations to beconsistent with the spectral data. In either case, a folded conformationappears to be highly favored under these conditions.

Fournie-Zaluski er al. (11) investigated the conformations of the tet-rapeptide fragments Tyr-Gly-Gly-Phe, Gly-Gly-Phe-Leu, and Gly-Gly-Phe-Met in dimethylsulfoxide solution using proton NMR spectroscopy.Temperature dependence of the amide protons in each case suggested thatthe carboxyl-terminal NH was involved in an intramolecular hydrogenbond. These results and analysis of the backbone proton coupling con-stants indicated that all three compounds exist in a type I ,,-bendconformation.

[Leu ]enkephalins labeled with carbon- 13 in the carbonyl carbons wereprepared by Stimson er al (24). Using carbon and proton NMR, they founda low temperature dependence for the Leu'-NH and the Gly2-CO, insupport of a hydrogen-bonded ,,-bend structure. In constrast to the workof Khaled er al. (/6, see above), these workers found no evidence of aconcentration dependence. The values of the carbon-13 spin-lattice relaxa-tion times of all of the carbonyl carbons were essentially identical, lendingfurther credence to the existence of a folded structure. With the carbon-13labels present, these workers were able to measure carbon-proton cou-pling constants, from which they ruled out type I', type II. and type II',,-bend conformations; they interpreted their data in terms of a type I,,-bend.

Han et al. (13) used laser Raman spectroscopy to examine the conforma-tion of [Leu]enkephalin and carbon-I3 labeled derivatives in dimethyl-sulfoxide solution. Analysis of the amide bands indicated the presence of a"-bend conformation, but it was not possible to determine from theseexperiments the type of ,,-bend(s) present.

A group of French workers (25,26) prepared [Leu]enkephalin enrichedin nitrogen- 15. Using nitrogen-IS NMR in dimethylsulfoxide solution, theyobserved that nitrogen spin-lattice relaxation times were consistent with afolded structure. On the basis of nitrogen-proton coupling constants, they


ruled out a type I ,,-bend conformation and proposed that a type II' ,,-bendis favored in solution.

These conflicting results may be due to the fact that the measuredproton-proton, carbon-proton, and nitrogen-proton coupling constantswere interpreted as though they arise from a single conformation, whereasthere may be multiple conformations in solution that interconvert rapidly.If the latter is occurring, th'\, coupling constants observed will be aBoltzmann weighted average over all of the conformations present. In fact,several authors have argued for the existence of multiple conformations indimethylsulfoxide solution.

[Leujenkephalins having stereospecific deuterium labels on the glycineresidues were prepared by Fischman er al. (27). Using proton-protoncoupling constants. they found no evidence for a single preferred con-formation in solution and suggested that conformational averaging isprobably taking place.

Higashijima and co-workers (28-30) have carried out extensive protonand carbon NMR studies of [Met]enkephalin and [Met]enkephalinamidein dimethylsulfoxide solution as a function of temperature and concentra-tion. Like Khaled et al. (/6), these workers ohserved significant concentra-tion dependence of the NMR spectra. Concentration-dependent shiftswere largest for the Tyr1 and Met' resonances. In variable-temperaturestudies, these workers confirmed the low temperature dependence of theMet'-NH proton. but they pointed out that the temperature dependence isnonlinear. Furthermore, several of the a-protons also exhibit temperaturedependence. These anomalous temperature dependencies were attributedto aromatic ring current effects occurring in dimeric forms (e.g., Fig. 12-3).In addition to dimeric forms, these workers found evidence for a foldedconformation in dimethylsulfoxide. When Gd(III) was used as a relaxationprobe, it was bound to the C-terminal carboxylate group; the distance-dependent relaxation was greater for the Tyr1 residue than for the Gly2,Gly3, and Phe4 residues. Further, when ammonium perchlorate was addedto disrupt the intramolecular head-to-tail attraction the Gd(III) relaxationfollowed the order Met' > Phe4 > Gly3 > Gly2 > Tyr1. They concludedthat there exists in solution a group of conformations that interconvertrapidly.

A similar conclusion was drawn by Oi Bello and co-workers (31) in theirproton NMR study of' enkephalin analogs containing y-aminobutyric acid(GABA). Analogs incorporating GABA into position 2 or position 5showed evidence of both folded and extended conformers in dimethyl-sulfoxide solution.

More recently, Renugopalakrishnan er al. (32) published studies on[Leu]enkephalin and [Metjenkephalin in dimethylsulfoxide solution

1

\10 12 Physical Chemistry and Molecular Modeling of the Enkcphalins

OH9'

""H

@_H,N N,COp ~"O,'.. /::0

~N,H H'N

CH,S) 0' ~-io

Fig. 12-5. Folded conformation of [MetJenkephalin proposed by Zctta and Cabassi

(reference 34).

using infrared and laser Raman methods. Their interpretation differedfrom that of Han et al. (I3, see above). The amide 1 band that Han et al.attributed to a {Hurn is proposed by Renugopalakrishnan and co-workersto represent a f3-sheet structure (i.e., extended conformation, associated asshown in Fig. 12-3). One may conclude that infrared and Raman spectraare not sufficiently definitive (or not sufficiently well understood at present)to permit detailed conformational conclusions to be drawn.

Anteunis and co-workers (33) carried out a proton NMR study of[Met]enkephalin in dimethylsulfoxide-water (2:1). They found that titra-tion of the amino group affected the resonances of the methionine residue.Titration of the carboxylate group affected the resonances of the tyrosineresidue. These findings suggest that there exists a folded conformationstabilized by head-to-tail interactions at intermediate pH.

Zetta and Cabassi (34) also examined [Met]enkephalin in dimethylsulf-oxide and dimethylsulfoxide-water mixtures by proton NMR. When thedimethylsulfoxide concentration was 60 mol% or greater, the Met5-NHproton was found to be intramolecularly hydrogen bonded and theGly3-NH to be shielded from solvent. These workers proposed theconformation shown in Fig. 12-5 to account for the observed spectralproperties.

The hexapeptides Tyr- Tyr-Gly-Gly-Phe-Met, Phe- Tyr-Gly-Gly-Phe-Met, Lys-Tyr-Gly-Gly-Phe-Met, and Gly-Tyr-Gly-Gly-Phe-Met all retainsignificant opiate receptor binding and analgesic activity that appears to bedue to the intact peptide (35). These compounds all show proton NMRevidence (backbone proton-proton coupling constants and Met-NHtemperature dependence), which supports a f3-bend conformation for theGly-Gly-Phe-Met segment in dimethylsulfoxide solution. This suggeststhat the relatively rigid f3-bend portion can still bind to the receptor, while

III Solution Conformations \11

the N-terminal X-Tyr segment is sufficiently flexible to permit interactionwith the receptor.

The enkephalin anal~g ,!,yr-o-Ala-Gly-Phe-Met was examined byNiccolai et ~I. (36) using proton NMR in dimethylsulfoxide solution.Proton spin-lattice relaxation rates indicated that this compound has arelatively rigid backbone. Nuclear Overhauser enhancement measure-ments showed that the methyl groups of o-Ala and Met are in closeproximity in solution, supporting ~he existence of a f3-bend conformation.

Kessler and Holzemann (37,38) conducted proton NMR studies ofcyclo-[Leu]enkephalin and cyclo-[Met]enkephalin in dimethylsulfoxidesolution. On the basis of the temperature dependence of amide protons,proton-proton coupling constants, and studies on model compounds, theyproposed a y, y-conformation (Fig. 12-6). Furthermore, they suggestedthat acyclic enkephalins might adopt a similar conformation in solution.Unfortunately, these workers were unable to determine whether thesecyclized compounds have biological activity due to their poor watersolubility.

Roques and co-workers (39) obtained evidence for a folded conforma-tion in the analog Tyr-o-Met-Gly-Phe-Pro In dimethylsulfoxide solutIOn.This compound ha~ no amide NH on the fifth amino acid residue tohydrogen bond. A strong head-to-tail interaction was suggested by theobservations that titration of the amino group strongly affected the Pro'resonances and that titration of the carboxylate strongly affected the Tyr'resonances.

A number of JL-selective enkephalin analogs were studied by Fournie-Zaluski et al. (40). These compounds generally had a o-amino acid inposition 2, and the fourth and fifth residues were replaced by hydrophobicamide groups. Proton NMR spectra in dimethylsulfoxide solution indicated

HO

,

1

Fig. /2-6. 'Y,y-Conformation of cyclo-enkephalins proposed by Kessler and Holzemann(references 37, 38).


a highly folded conformation for theauthors considered the folded form tomorphine.

Gairin ef al. (41) carried out proton NMR studies in dimethylsulfoxidesolution on Tyr-o-Ala-Gly-Phe-Nva, Tyr-o-Ala-Gly-Phe-Met, and theirC-terminal ami des (Nva = norvaline). The amides. which showed

I"selectivity, gave evidence of having different solution conformations andmore conformational rigidity than their parent compounds.

Measurement of energy transfer between donor and acceptorfluorophores permits an estimate of the intramolecular distance betweenthe two groups. In the case of the enkephalins, such experiments providean estimate of the average distance between the two aromatic rings. Suchfluorescence measurements have been carried out in aqueous solution, forthe most part, but Reig ef al. (42) found a phenyl-phenyl distance of 9.4 Afor ethanol solutions of Tyr-o-Pro-Gly-Phe-Leu-OEt and Tyr-o-Pro-Gly-Phe-Met-OEt. Garcia-Anton and co-workers (43) obtained a distance of10.8 A for Tyr-o-Met-Gly-Trp-Pro in ethanol. Such distances require atleast some folding of the peptide backbone.

[Met ]enkephalin in trifluoroethanol solution was examined using ultra-violet and circular dichroism spectra (44). Lack of temperature depen-dence was interpreted to mean that there is no ordered structure underthese conditions. In addition, the pH dependence of the spectra wasexamined; this study indicated that there is no evidence for involvement ofthe tyrosine hydroxyl group in intramolecular hydrogen bonding.

Numerous studies have been made of side chain conformations of theenkephalins in organic solvents. On the basis of spin-lattice relaxation timemeasurements, Bleich ef al. (21,45) concluded that the tyrosine side chainof [Met]enkephalin is conformationally restricted, whereas the phenylala-nine and methionine side chains undergo rapid motion in dimethylsulfox-ide solution. Combrisson and co-workers (19) came to a similar conclusionfor the same compound in a I: I mixed dimethylsulfoxide-water solventsystem.

In their study of [Leu]enkephalin in dimethylsulfoxide, Garbay-Jaureguiberry ef al. (23) concluded from proton-proton coupling constantsthat all three rotamers of the tyrosine side chain coexist in solution, withrotamer I predominating (see Section I for the conventions used todescribe side chain rotamers). Similarly, they found rotamer I to pre-dominate for the phenylalanine side chain, with lesser amounts of rotamers

"and III. However, they concluded that only rotamer [ was significantly

populated for the leucine side chain. On the basis of carbon-13 spin-latticerelaxation times, they determined that the tyrosine aromatic ring does notundergo reorientation around the Cy-C, axis; the phenylalanine and

I"-selective compounds. Thesebe similar in overall shape to


leucine side chains appeared to have significant internal rotationalfreedom.

For the analog Tyr-o-Met-Gly-Phe-Pro in dimethylsulfoxide, Roquesand co-workers (39) determined side chain rotamer populations fromproton NMR coupling constants. They found all three rotamers populatedfor the tyrosine side chain, while rotamer I predominated to the extent ofabout 60% for the phenylalanine slOe chain. Again, carbon-13 spin-latticerelaxation times indicated limited rotation for the tyrosine side chain.

Using nitrogen-15 NMR and nitrogen-15 labeled [Leu]enkephalins,Garbay-Jaureguiberry and co-workers (26) studied the rotameric states ofthe phenylalanine and leucine side chains. On the basis of proton-nitrogen, proton-carbon, and proton-proton coupling constants, theseinvestigators found the following ratios of rotamers 1111I11I:phenylalanine,65/10/25; leucine, 95/015.

Stimson ef al. (24) carried out a similar study of [Leu ]enkephalin indimethylsulfoxide using proton and carbon NMR. They did not distinguishbetween conformations I and", but they found that these two conformerspredominated over rotamer III for all three side chains in [Leu]enkephalin.Rotamers I and" accounted for 80% of the rotamer population of thetyrosine residue, 90% of the phenylalanine rotamers, and 100% of theleucine rotamer population.

In contrast, Jones ef al. (20) found substantial populations of all threerotamers for the methionine side chain in [Met]enkephalin. Using proton-proton coupling constants, these workers found the ratio of 1111I11I to beabout 43/40117.

Niccolai ef al. (36) used proton NMR to probe the side chain conforma-tions of Tyr-o-Ala-Gly-Phe-Met in dimethylsulfoxide solution. They re-ported that the o-alanine, phenylalanine, and methionine side chains havesubstantial internal motion, while the tyrosine side chain is not freelyrotating.

Kobayashi and co-workers (46-49) have carried out extensive protonNMR studies on [Met]enkephalins having deuterium label(s) on the Cland{3carbons of the tyrosine and phenylalanine residues. Using these labeledcompounds, they carried out an analysis of the tyrosine and phenylalanineside chain rotamers as a function of temperature and of solvent polarity.Fig. 12-7 shows the effect of temperature on the side chain rotamerpopulations in dimethylsulfoxide solution. As expected, increasing temper-ature increases the populations of less stable conformers at the expense ofmore stable ones in the case of phenylalanine. However, the most stabletyrosine rotamer became more populated at higher temperature. Theseworkersattributedthis anomalous behavior to a change in the equilibriumbetween folded and extended conformations with change in temperature.

1

1.0

~0.8.3., 0.8~0

~.0.4

II~I

"'" 0.2 ill

5 10 15 20

\24 12 Physical Chemistry and Molecular Modeling of the Enkephalins

I

illn

20 40 60 80 100 20 40 60 80 100

Temperature (oC)

Fig. 12-7. Effect of temperature on the rotamer populations of Tyrl and Phe4 side chains

of [Metjenkephalin in dimethylsulfoxide solution (references 47, 48).

Fig. 12-8 shows the effect of a change in solvent polarity (reported as thelogarithm of the dielectric constant) on the rotamer populations in thesecompounds. Among the phenylalanine rotamers, conformation 111consti-tutes about 15% of the total throughout the range of polarities studied.The major conformer (I) increases in importance as the solvent polarityincreases, with a concomitant decrease in the population of conformer II.For the tyrosine rotamers, conformation 111 again makes up a fairlyconstant percentage of the total population (about 20% in this case).Unlike phenylalanine, however, the rotamer I population decreases assolvent polarity increases, until rotamers I and II are present in aboutequal proportions in aqueous solution.

Overall, the evidence regarding the conformation of enkephalins inorganic solvents is probably best interpreted in terms of multiple con-

05

~'r~

0

'n .'ill~~

o 1log €

2

log €

PhF~g. ,12-8. ,Effect of a solvent di:le~tric .constant on the rota mer populations of Tyrl ande side chams of fMet)enkephahn In dimethylsulfoxide solution (references 46, 48).


formations, including one or more folded forms. The results give someindication of the conformational possibilities but do not permit identifica-tion of an "active conformation."

B. Studies in Aqueous Solution

Numerous studies (e.g., 16,21,30,50;51) using NMR, ultraviolet, circu-lar dichroism, and fluorescence spectroscopy have indicated apparentconformational differences on going from organic to aqueous solventconditions. One may argue that the aqueous environment is more relevantto the physiological situation, although the extent of solvation of themolecule at its receptor site is open to question. Many of the sametechniques that were described in the previous section for enkephalins inorganic solvents have also been applied to aqueous solutions. In addition,interactions with metal ions and lipid systems have been investigated.

An important consideration when studying conformational behavior inaqueous solution is the ionization state of the molecule. As would beexpected, the neutral form of the enkephalins was shown (using infraredand laser Raman spectroscopy) to exist as the zwitterion in aqueoussolution (14). This result was in contrast to the finding (see above) of bothuncharged and zwitterionic forms in dimethylsulfoxide solution.

Directly related to the question of ionization state is the dissociationbehavior of the acidic and basic groups in the molecule. A number of pKadeterminations have been reported for [Metjenkephalin. For the N-terminal amino group, values of 7.75 (28), 7.2 (52), and 7.7 :t 0.3 (53)have been reported. Carboxylate pKa values reported include 3.50 (28),3.55 (52), 3.2:t 0.3 (53), and 2.8 (54). The tyrosine hydroxyl ionizationwas reported to occur at 10.2 (50), 10.4 (52), 1O.2:t 0.2 (44), and1O.5:t 0.3 (53).

Fischman et al. (27) carried out proton NMR studies on [Leu]enkepha-lins having stereospecific deuterium labels on the glycine" carbons. On thebasis of proton-proton coupling constants, they argued that there areprobably many conformations rapidly interconverting in aqueous solutionand that the observed coupling constants are the result of conformationalaveraging.

Spirtes and co-workers (44) drew a similar conclusion regarding[Met]enkephalin in aqueous solution. The observation that the circulardichroism spectrum was not affected by temperature suggested theabsence of an ordered structure. Using laser Raman spectroscopy, Han etal. (13) also concluded that multiple conformations exist in aqueoussolution.

Studying [Met]enkephalin in aqueous solution by proton and carbonNMR, Higashijima and co-workers (28) found that titration of the

i

526 12 Physical Chemistry and Molecular t\.1odeling of the Enkcphalins III Solution Conformations m

N-terminal amino group did not affect resonances of the methionineresidue and that titration of the methionine carboxylate did not affecttyrosine resonances. These results indicate that the two end groups are notin close proximity in solution and that monomeric extended forms pre-dominate under these conditions. Furthermore, none of the amide NHresonances gave any evidence of intramolecular hydrogen bonding orshielding from solvent.

In a natural abundance nitrogen-IS NMR study of [Metjenkephalin,Higuchi et al. (54) also carried out a titration of the methionine carboxylategroup. This titration had no effect on the tyrosine nitrogen chemical shift,again suggesting that the end groups arc not close together in aqueoussolution.

Miyazawa and Higashijima (30) provided further evidence for anextended conformation in aqueous solution. Spin-lattice relaxation rateenhancement by Gd(lII) was found to be greatest for methionine protons[where the Gd(III) was bound to the carboxylate group] and to decreasecontinously for protons on Gly3, Gly', and Tyrl Since relaxation enhance-ment is dependent on distance through space, it would appear thatextended forms predominate.

Zetta and Cabassi (34) examined the proton NMR spectra of [MetJen-kephalin in water, dimethylsulfoxide, and mixed solvents. They foundextended conformations predominant in aqueous solution and in water-dimethylsulfoxide mixtures containing 40 mol% or more of water.

Infrared and laser Raman spectra of [Leulenkephalin and [Met len-kephalin in aqueous solution were examined by Renugopalakrishnan andco-workers (32). On the basis of comparisons with spectra of modelcompounds, they suggested that [Met]enkephalin exists in a ,B-sheet(extended) conformation and that [Leu]enkephalin exhibits both ,B-sheetand type II ,B-bend conformations. They suggest that such conformationaldifferences may be related to receptor subtype selectivity.

In contrast to these indications that enkephalins adopt mainly extendedconformations in aqueous solution, other workers have interpreted theirresults in terms of folded conformations. Jones et al. (20), on the basis ofproton-proton coupling constants, proposed that [Met]enkephalin hasqualitatively the same folded conformation in water as in dimethylsulfox-ide. Tancrede et al. (55,56) measured spin-lattice relaxation times for[Met]enkephalins having the carbon-13 label in Gly2 or Gly3 They foundthat Gly3 motion was more restricted than that of Glyl, the opposite ofwhat would be expected for an extended, unordered conformation.

Using paramagnetic probes [Gd(lII) bound to the carboxylate group andCr(CN). -3 bound to the amino group], Levine et al. (53) measuredaverage distances between the probe and protons on [Met]enkephalin.

They compared these measured average values with calculated values for afully extended conformation and found the measured distances to be up to0.8 A shorter. This observation indicated to them that folded conforma-tions contribute to the overall conformational population in aqueoussolution, even though no head-to-tail or intramolecular hydrogen bondinteractions could be demonstrated directly. Zetta et al. (57) were alsounable to find direct evidence for intramolecular hydrogen bonds orhead-to-tail interactions, but they found that the Gly-Phe-Met segmenthad less conformational freedom than the Tyr-Gly segment, again consis-tent with the existence of folded conformations.

Fluorescence spectroscopy has been applied extensively to aqueoussolutions of enkephalins and enkephalin analogs. This approach permits anassessment of the average distance separating two aromatic groups ina molecule. For [MetJenkephalin and [LeuJenkephalin, Kupryszewskaet al. (58) observed both sensitized fluorescence of the acceptor andquenching of donor fluorescence. From these measurements, they calcu-lated average phenyl-phenyl distances ranging from 7.5 to 8.7 A, depend-ing on the method used.

Schiller and co-workers (59-63) have carried out fluorescence measure-ments on several [Trp4]enkephalins, which retain substantial analgesicactivity. Intramolecular Tyr- Trp distances in these compounds rangedfrom 8.8 to 10.7 A, with a mean value of 9.3:t 0.2 A. This result isconsistent with either a single folded conformation in solution or anaveraged value for many solution conformations, including significantcontributions from folded conformers. In either case, the results areconsistent with one or more folded conformations, that is, thepeptides are not fully extended all the time in aqueous solution. Since the9.3-A average distance is maintained even at pH 1.5, the head-to-tail ionicattraction between the charged end groups is not required to stabilize thefolding.

Other workers have found similar results using fluorescence spectra.Garcia-Anton el al. (43) found a Tyr- Trp distance of9.0 A for Tyr-D-Met-Gly-Trp-Pro-NH2 in water. Using [4'-NH,-Phe4]enkephalin, Siemion andSzewczuk (64) observed a phenyl-phenyl distance of 10 A. Guyon-Gruaz(65) and co-workers carried out similar measurements on enkephalinderivatives having C-terminal dansyl substituents. They obtained tyrosine-dansyl distances in water and in trifluoroethanol solution of 12.4-14.9 A,which again requires at least some contribution from folded conformers.

Schiller (60) reported, on the basis of fluorescence spectra, that thetyrosine hydroxyl group is not involved in hydrogen bonding, since the

phenol fluorescence is not quenched in [Trp4]enkephalins. On the otherhand, Filippi et al. (66) compared fluorescence yields of [Leu]enkephalin

!II Solution Conformations 529

10 1.0A B

0.8 0.8~0.~ ----.

0.6 06., I~0

IT~.O. OA

~I 00 0 II

'" 0.2 0.2...... I -, _aAm ,..-. .8 . .... ....m

528 12 Physical Chemistry and Molecular Modeling of the Enkcphalins

and its Ser'-analog to those of the model compound tyrosinamide andconcluded that the decreased fluorescence (10-15% lower) strongly sup-ported the presence of intramolecular hydrogen bonding involving thehydroxyl group.

Soos et al. (67) considered the aqueous solution conformation ofenkephalins to consist of a mixture of random and J3-bend conformers.They determined the circular dichroism spectra of [Met]enkephalin and ofthe fragments Tyr-Gly-Gly and Gly-Gly-Phe, then subtracted the spectraof the latter two fragments (which presumably have random conforma-tions), and considered that the remaining CD spectrum was due to J3-bendconformation. Repeating the CD measurements for a series of fiveen kephalin analogs, these workers found a correlation (correlation coef-ficient = 0.94) between the "J3-bend content" and the measured IDsovalues in guinea pig ileum preparations. Interestingly, there was notsignificant correlation with activity in mouse vas deferens. These authorssuggested, on this basis, that the J3-bend conformation is required foractivity in the guinea pig ileum receptor population, but not for the mousevas deferens receptor population.

Overall, the evidence amassed to date appears to be most consistent withthe interpretation that the enkephalin backbone is highly flexible inaqueous solution. Both extended and folded forms probably exist inequilibrium.

Side chain conformers have also been studied extensively in aqueoussolution. Khaled et al. (68), using carbon-13 NMR, observed that thetyrosine y-atom showed unusual titration behavior at high pH. Theyattributed this result to a conformational change in the tyrosine side chainat higher pH. On the basis of spin-lattice relaxation times, proton exchangerates, and temperature and pH effects in the NMR spectra of deuterium-labeled enkephalins, Bleich and co-workers (21,69) determined that thetyrosine side chain motion is quite rigidly fixed with respect to the peptidemain chain. On the other hand, they found that the phenylalanine andmethionine side chains undergo rapid motion.

Kobayashi and co-workers (46-49), using deuterium-labeled [Met]en-kephalin, determlOed the proportions of rotamers I, II, and III for thetyrosine and phenylalanine side chains of [Met]enkephalin in aqueoussolutIOn. FIg. 12-9 illustrates the existence of all three rotamers of tyrosineand phenylalanine over a wide range of pH values.

Circular dichroism and NMR spectroscopy have been applied to thestudy of the solution conformation(s) of larger peptide analgesics such asthe endorphins, dynorphin, and lipotoropin (see Chapter II for structures).UslOg carbon-I3 NMR spectra, Tancrede et al. (55,56) found a-endorphinto exist in a flexible random coil structure in aqueous solution. Addition of

o 5 10 0 5 10pH pH

Fig. 12.9. Effect of pH on the rotamer populations of Tyr1 and Phe4 side chains of[Met}enkephalin in aqueous solution (reference 48).

lipids had no effect on spin-lattice relaxation times, chemical shifts, or linewidths, with the exception of phosphatidylserine at slightly acidic orneutral pH. In the presence of phosphatidylserine, spin-lattice relaxationtimes were found to be highly dependent on solution pH.

Hollosi and co-workers (70) carried out circular dichroism studies ofJ3-endorphin in water and in trifluoroethanol. In trifluoroethanol, which isa helix-promoting solvent, these workers found a helical structure, prob-ably near the C-terminal region. Comparisons with model compoundssuggested that the helical structure was stabilized by interaction with theN-terminal amino group. In contrast, J3-endorphin showed little tendencyto form a helical structure in aqueous solution.

Levine et al. (53) found the proton NMR spectrum of J3-endorphin inwater to differ significantly from that predicted for the peptide in a randomcoil conformation. The existence of some conformational restraintswassupported by relaxation measurements using Gd(III) ions. In comparisonto J3-endorphin, the Met5-sulfoxide derivative showed less opiate activityand less tendency to form a-helix in trifluoroethanol (7/ ,72).

A J3-endorphin analog was prepared by Taylor et al. (73) in whichresidues 1-19 were the same as in J3-endorphin, while the remainder of theresidues were selected on the basis of their ability to promote helixformation. The CD spectrum does, in fact, show helical forms, and thesynthesized compound 'was shown to have receptor affinities two to threetimes that of the parent compound.

Studying J3-endorphin in trifluoroethanol, Hammonds et al. (74) foundthat a considerable a-helix structure is present for J3-endorphin, whilethese authors could find no helical structure for [Met]enkephalin. Bewleyand Li (75) examined J3-endorphin fragments of varying size in aqueous


solution using ultraviolet spectroscopy. They determined that at least nineamino acid residues had to be present in order to demonstrate orderedstructure. In /3-endorphin, they found evidence for a tertiary structurearound the Tyr1 and Phe4 side chains. The a-amino group, Lys'", andthe fragment Thr6-SerlO appeared to be involved in stabilizing a foldedform.

In a series of circular dichroism studies of /3-endorphin and /3-lipotropinin aqueous solution (76-79), there was little evidence of any secondarystructure in water. This conclusion was supported by viscosity measure-ments and sedimentationcoefficients,whichwere consistentwith a randomcoil conformation. Helical structure appeared to be present in methanolsolution or when lipids or sodium dodecyl sulfate were added to the solu-tion. The secondary structure induced by addition of lipid was disruptedon addition of calcium ion. Lipotropin was also found to acquire somehelical character when the solvent was trifluoroethanol (80).

Maroun and Mattice (81) carried out circular dichroism investigations ondynorphin. They found no ordered structure for this compound in aqueoussolution. Addition of phospholipid had little or no effect, but addition ofsodium dodecyl sulfate induced the formation of a-helical regions. Schiller(63) prepared a synthetic dynorphin fragment having tryptophan inposition 4. Unlike the enkephalins (see above), fluorescence spectrashowed that the Tyr1_Trp4 average distance was at least 15 A (compared toabout 10 A for the enkephalin analogs).

It has been proposed that phospholipids may be intimately connected tothe opiate receptor, and it has been shown that some lipids can bind opiateanalgesics stereospecifically (82,83). For this reason, several studies havefocused on the effects of phospholipids on en kephalin conformation.Behnam and Deber (84) examined the tyrosine and phenylalanine /3-proton resonances of [Met]enkephalin in the presence of Iysophosphatidylglycerol micelles. They found that the tyrosine resonances broaden byabout 5.5 Hz. The two phenylalanine resonances shifted 30 and 4 Hz,respectively. There was no significant change in the a-/3 proton-protoncoupling constants, however, indicating no change in the side chainrotamer populations.

In a carbon NMR study of [Met]enkephalin in the presence of phospha-tidylserine, Jarrell et al. (85) found evidence for enkephalin-lipid interac-tions. The spin-lattice relaxation times were altered, indicating a change inthe degree of molecular motion in solution. Salt and morphine were shownto interfere with the interaction. The pH optimum for binding was in theslightly acidic range. The binding was shown to involve the N-terminalamino group but not the tyrosine hydroxyl C-terminal carboxyl group.Binding constants for this process were very low.


l 0

o'l-Ir:~l-I 0FN N JL-NH

r CH " 'i: ;. :tC'H,HO-C H '\ .:

'~+.'6 4 ,N --0

NHH Ii '-~'c ""\l (-~ 1 0R

Fig. 12.10. Proposed structure of the copper (II)-cnkephalin complex (reference 90).

.1

Bleich and co-workers (86) measured the effee{ of [Met ]enkephalin onthe spin-lattice relaxation times of the lipid resonances. They monitoredthe proton resonances of the choline methyl groups, the alkyl chains, andthe w-methyl groups in vesicles of /3,y-dimyristoyl-l-a-Iecithin. Theyfound that enkephalin alters the relaxation times for these resonances,indicating some interaction. However, the interaction was found to benonspecific, since it was also shown to occur with tetraglycine.

There has been considerable interest in en kephalin interaction withmetal ions, beginning with the circular dichroism study of Poupaert et al.(52). Addition of sodium or potassium ions caused changes in the carbonylregion of the spectrum, leaving the aromatic region unchanged. Theinteraction with sodium was weak, but was considered to be potentiallysignificant.

Divalent cations produce much more stable complexes, as demonstratedin a number of studies. Hollosi and co-workers (87) found that calcium andmanganese form 1:1 complexes with several enkephalin analogs. Usingproton NMR, Haran et al. (88) found that zinc ions affect chemical shiftsand coupling constants of [Met]enkephalin, implying that a conforma-tional change was induced. It was shown (89) that divalent metal ions havea greater effect on enkephalins than on enkephalinamides. This is consis-tent with the expected interaction of the cation with the carboxylate group.

Addition of divalent copper was shown (90) to affect selectively thefollowing carbon NMR resonances: Met' carboxylate and C-a; Tyr1carbonyl and C-a; Gly2 C-a; Gly3 C-a. The structure shown in Fig. 12-10was proposed for the complex. Sharrock et al. (91) demonstrated that,although the copper complex is a relatively strong one, it has very littleeffect on the biological activity and the in vitro receptor binding.

Aided by proton,. carbon, and aluminum NMR, Mazarguil andco-workers (92) studied the binding of aluminum (III) ions to [Leu Jen-kephalin. They found evidence for two binding sites, the first involving thetyrosine carbonyl and the C-terminal carboxylate, and the second involv-ing the N-terminal amino group. Aluminum binding altered the tempera-ture dependence of the amide protons in dimethylsulfoxide solution,suggesting that the /3-bend conformation was disrupted.

\32 12 Physical Chemistry and Molecular Modeling of the EnkephaJinsIV Molecular Modeling Studies IJJ

IV. Molecular Modeling Studiescharacterized by two transannular hydrogen bonds, one involving Orn'-NH and Orn'-CO and the other involving Leus-NH and Gly3-CO.Molecular mechanics-based conformational energy calculations on yet athird cyclic analog in this class, Tyr-cyclo[N-y-o-Dbu-Gly-Phe-Leu], iden-tified a low-energy conformer resembling the type II' l3-bend modelproposed by Clarke and co-workers (108). This conformer lacks a hy-drogen bond involving the Leu5-NH and Dbu-CO)groups that should beexpected by analogy to the other two cyclic compounds.

Overall, the backbone conformations of Tyr-cyclo[N-.-o-Lys-Gly-Phe-Leu] and Tyr-cyclo[N-l>-o-Orn-Gly-Phe-Leu] can be taken as necessary butnot sufficient constraints to define the bioactive conformation. Side chainflexibility and the possibility of conformational changes on binding couldnegate the structural information realized from these restricted analogs.Taken literally, the difference in backbone conformations of Tyr-cyclo[N-.-o-Lys-Gly-Phe-Leu] and Tyr-cyclo[N-l>-o-Orn-Gly-Phe-Leu] suggestthat the geometry of the opioid receptors can accommodate at least twodifferent en kephalin backbone conformations.

The high conformational flexibility of enkephalin has prevented acomplete conformational analysis in terms of a systematic search involvingall torsional rotations. Research has focused on conformational strategiesto overcome the uncertainty associated with high conformational flexibil-ity. Three types of general strategies, not necessarily independent of oneanother, have emerged:

I. Identifying and exploring the major determinants of conformationalspecificity.

2. Comparing common conformations available to active analogs butunaccessible to inactive congeners.

3. Matching low-energy conformations of enkephalins to rigid opiateslike morphine and its derivatives.

With few exceptions, all conformational energy calculations have beenperformed using molecular mechanics (109). Many calculations have beenbased on application of the Empirical Conformational Energy of Peptidesand Proteins (ECEPP) program (110). The effect of solvent has not beenincluded in any of the conformational analyses. This is an important pointto keep in mind with regard to the relative stability of folded conformationscompared to extended structures. In free space, folded conformations cangain added stabilization energy from both dispersion and electrostaticinteractions involving distant atoms with respect to primary structure. Thisis clearly not possible in extended conformations, where favorable solute-solvent interactions have the potential to overcome favorable folded

intramolecular effects. The conformational analyses of the enkephalins are

A consequence of the high conformational flexibility in the enkephalinfamIly has been to focus computation-based research on conformationalbehavior and not thermodynamic features, as can be derived from quan-tltalIve structure-activity relationship (QSAR) approaches. The theoreti-cal conformational energy calculations on enkephalins reported belowshould be reviewed in light of the recent syntheses and at least partialexpenmental conformational characterization of conformationally re-stncted ~nalogs (37,38,93-95), some of which displayed significant anal-gesIc activIty In one or more screens (94-105).

In particular, the backbone-restricted analog, Tyr-cyclo[N-.-o-Lys_Gly_Phe-Leu] (FIg. 12-1 I) has been studIed by proton NMR in dimethylsulfox_,?e. Nonequlvalence of the Gly3

" protons suggests some rigidity of thenng str~cture. A l3-bend backbone conformation at Phe4 and Leus, whichISstablhz,ed by Intramolecular hydrogen bonding involving the N-. protonof o-Lys and the carbonyl group of Gly3, has been suggested from anan~lysis of the coupling constants and the temperature dependence of thear'."de protons: The proposed conformation is shown in Fig. 12-11. Whilethis conformatIOn has .conslderably more rigidity than open-chain analogs,srgnrficant conformatIOnal freedom still exists regarding the relativeonentatlOns of the functional groups on the side chains. The cyclic analogTyr-cYclo[N-l>-o-O~n-GIY-Phe_Leuj has been shown to retain a singleconformatIOn In dImethylsulfoxide solution (107). This conformation is

Fig. 12-11. Conformation ofTyr-cyclo-N-t:.D-Lys-Gly_Phc_Leu proposed by Kessler andHolzemann (reference /06).

114 12 Physical Chemistry and Molecular Modeling of the, Enkcphalins

further complicated by the charge state assigned to a molecule. Withoutknowing the charge state at the receptor, the assignment of chargesremains an intrinsic assumption in any such study.

Isogai el al. (Ill) carried out a conformational analysis of [Met]en-kephalin and concluded that the lowest-energy conformation involves afolded conformation characterized by a type II' bend in the Gly3-Phe.position. This conformation is stabilized by an intramolecular hydrogenbond between the carbonyl group of Gly3 and the hydroxyl group on thetyrosyl side chain. Tyrosine fluorescence studies in water and butanol (60)and pK, determination of the tyrosine hydroxyl in water (44) suggest thatthis calculated conformation is not highly populated in these solvents eventhough the structure is consistent with some NMR data (17). Thecalculated low-energy conformer having a type II' ,l3-bend allows anL-alanine but not a o-alanine to be substituted for Glyz. It has been foundthat both L-Ala2 and o-Alaz analogs retain high binding potencies in both J.Land Ii receptor assays. On this basis, Isogai el al. came to the conclusionthat their lowest -energy conformer is not the bioactive form.

Momany (112) followed up the study of Isogai elzal. with extensiveconformational analyses of [Metjenkephahn, [L-Ala ,Met ]enkephahn,and [o-Alaz,Met'jenkephalin using the ECEPP program. The enkephahnanalogs were assigned different charged end groups to assess the role ofcharge state on conformation. The lowest-energy conformer f~und for thehighly active [o-Alaz,Met']enkephalin differs from the (sogal conforma-tion in that the hydroxyl group on tyrosine is not mvolved m an mtra-molecular hydrogen bond. Unfortunately, this conformation is probablynot the active conformation. It is incompatible with substitution ofa-methylphenylalanine in position 4 and a-aminoisobutyric acid in posi-tion 2, both of which result in active analogs (1).

The minimum-energy conformations of each residue were used togenerate 400 starting conformations in a conformational analysis of thezwitterionic form of [Met]enkephalin (113). The Boltzmann probablhtleswere computed for the resulting conformational states. Fifteen of the 400conformers account for 97% of the total probability of state occupancy.There is considerable variability among the types <jfconformations withinthis set of 15. Both folded and extended conformations were found, whichled the authors to propose an equilibrium of conformer states in solution.

Monte Carlo computer simulation has been employed to sample confor-mational space available to [Leujenkephalin (114,115). Different ionicforms of the molecule give rise to different conformational distributions.The cationic form consists mainly of extended conformations such that thecalculated ensemble average NH-CH proton-proton coupling constantsare in good agreement with corresponding experimental values at low pH.

I'II

~

!

IV Molecular Modeling Studie~535

The zwitterionic form of the peptide gives rise to predominantly foldedconformations that are stabilized by terminal group electrostatic interac-tions.

Maigret and Premilat (116) followed up on their initial Monte Carlocalculations in an attempt to group conformers into common classes usingcluster analysis. Five common classes of enkephalin conformers werefound for both ionic states. Maigret and Premilat concluded that thesolution conformational behavior of en kephalin can be represented by theidentified common classes of conformers.

The Monte Carlo strategy was also employed by Demonte el al.(117,118) in a conformational analysis of some [Trp.]enkephalin conge-ners. The singlet-singlet energy transfer efficiencies between Tyrl and Trp.,which are distance dependent, were determined in aqueous solution byfluorescence spectroscopy for the zwitterionic form of [Trp.,Met']-en kephalin , [o-AlaZ, Trp. ,Met']enkephalin, [AlaZ,Trp. ,Met5jenkephalin,[Me-Trp.,Met5]enkephalin, and [Trp.,Me-Leu'jenkephalin. The corres-ponding average transfer efficiencies calculated from the Tyr'- Trp. intra-molecular distances based on the Monte Carlo-generated ensemble ofconformers are in good agreement with the experimental values. There isalso reasonable agreement between experimental and computed averageNMR proton-proton coupling constants for the backbone protons. TheMonte Carlo-based conformational analyses all point toward an equilib-rium distribution of conformer states in solution.

The tetrapeptide analogs Tyr-Gly-Gly-Phe, Tyr-o-Ala-Gly-Phe, andTyr-L-Ala-Gly-Phe were the subjects of Monte Carlo conformationalanalyses (I I). An equilibrium distribution of solution conformers ispostulated for Tyr-Gly-Gly-Phe and a highly populated, tightly foldedsolution conformer for Tyr-o-Ala-Gly-Phe on the basis of agreementbetween calculated and observed backbone proton-proton coupling con-stants.

The final strategy to be discussed here regarding the search for abioactive conformation is that of molecular comparison to rigid opiates.On the premise that the Tyrl and Phe. side chains of enkephalincorrespond as pharmacophores to the tyramine unit and the phenethylgroup, respectively, of PEa, some workers were led to determine low-energy enkephalin conformers that possess various amounts of structuraloverlap with PEa (119,120). Both molecular mechanics (119) and quan-tum mechanics (I20) methods were used to compute the conformatIOnalenergies. The enkephalin conformation that maximizes overlap with PEais high in energy, according to both studies.

.An alternate strategy was next adopted (120) in which a constramedconformational search was carried out"to overlap tyramine with Tyrl and to

\36 12 Physical Chemistry and Molecular Modeling of the Enkcphalins References537

conformation exhibits the T shape of morphine but is about 8 kcal/molehigher in energy than the calculated global minimum-energy conformer.Such a difference in energy is at the borderline regarding whether or notthe receptor interaction will overcome the intramolecular destabilization.

PEO

permit substitution of D-Ala, but not L-Ala, for Glyo. Thc 52 minimum-energy conformers identified by Isogai et al. (Ill) were used as startingpoints in this restricted conformational analysis. One of the resultingconformers met the conformational and overlap constraints and is only 3.5kcal/mole above the global minimum-conformer state. This conformer,superimposed on PEO, is shown in Fig.12-12. This proposed bioactiveconformation for [Metjenkephalin is characterized by a type II' j3-bendstructure such that considerable overlap is realized in the tyramine section,the side chain of Phe4 coincides with the phenethyl group, and the carbonylgroup of Met' shares a near common position with the methoxy group ofPEO.

Maigret and co-workers (121) also adopted a constrained energy mini-mization approach in the analysis of some tetrapeptide analogs of Tyr-D-Ala-Gly-Phe. Four alternative conformations derived from both ex-perimental and theoretical data were uscd in the energy minimizations.The Gly3 carbonyl group was fixed on the Coring hydroxyl of morphine,and the tyrosine residue was restricted to the tyramine locus. Inferentialarguments led these workers to select one of the four conformations as thethree-dimensional pharmacophore for the peptide at the

I'- receptor. This

.V. QSAR Studies

No published QSAR study of the enkephalins has been found by theseauthors. More generally, the use of classic linear free energy analyses forthe derivation of structure-activity relationships in peptide chemistry isremarkably scarce. The focal point in the analysis of peptides has been andcontinues to be conformational analysis.

One reason why little QSAR work has been done on pep tides is thedifficulty in assigning the appropriate state of ionization for thc biologicallyrelevant conditions. Partition coefficient, a, and other linear free-energydescriptors are quite sensitive to the ionic state of the peptide. In addition,linear free-energy descriptors, especially the partition coefficient, havebeen useful in characterizing drug action where transport and/or bioaccu-mulation are rate-limiting but continuous variables in dictating activity.Direct drug-receptor interactions are of secondary importance in thesesituations. In the casc of peptides, transport is often an all-or-none issue,that is, transport is a noncontinuous factor in bioactivity, and the specificityof the drug-receptor interaction is the critical event. Finally, linearfree-energy descriptors employ the implicit assumption that the individualcomponents are additive and that interactions between terms can bcignored. For molecules the size of pentapeptides, where intramolecularinteractions are often observed, such an assumption may no longer beappropriate in all cases.

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Index

A

6-AcetyJ-t.iodocodeine, x.ray crystallogra-phy, t67

Acetylisomethadol,411-414stereoisomers,412-413

Acetylmethadol,411-414dissociation constant, 451metabolism, 414receptor binding, 414stereoisomers, 412x-ray crystallography. 453

6-Acetylnormorphine, metabolite, 14, 18ACTH, contained in proopiomelanocortin,

4634-Acyloxy-4-arylpiperidines, 334-352; see

also Prodine, 3.Desmethylprodine,specific compound

methylation2,3-dimethyl. isomers, SAR, 346-3502,6-dimethyl, isomers, SAR. 346-3503,5-dimethyl, see lsopromedol2,S-dimethyl, see PromedolC-2 methyl, isomers. SAR. 348-349C-3 methyl. see Prodine

SAR, 337-352C-4 acytoxy, 337-338C-3 alkylation, 343-346C-4 aryl, 338dimethylation, see methylationC-2 methylation, 346-351; .fee aim

methylationC-3 methylation; see also Prodine; see

specific compoundN.I analogs, 338-341; see al.w

Norprodinesynthesis, 335-337

D-Ala!- 1)- I .eu~-enkcphalin

effect, respiration, 37relative affinity, for /) receptor, 34

[Ala2,Met~]enkephalin, molecular model-ing, 534

(o-Ala1,Mct~lenkephalin. molecular model-ing, 534

(o-Ala1,Met~)enkephalin amide. .\'('('DAME

(Ala1,Trp4,Met~lenkephalin. Monte Carlosimulation. 535

ID-Ala!,Trp4,Met~]enkephalin, Monte Carlosimulation, 535

Alfentanil, 3653-Alkyl-3-arylpiperidines, 354-356; see

also 4-Alkyl-4-arylpiperidines, Pro-fadol

antagonists, SAR, 358rigid analogs, 359-361ring contraction, SAR, 356-369ring expansion, 356

4-Alkyl-4-arylpiperidines, 352-354; seealso 3-Alkyl.3-arylpiperidines

antagonists, SAR, 353rigid analogs, 354, 359-361

AJletorphine, 137-138N.Allylnormetazocine, 31, 35, 278-279

effect, in chronic spinal dog, 31opiate receptor selectivity, 279relative affinity, for u receptor, 35

N.Allylnormorphine, see NalorphineN.AlIylnoroxymorphone, .fee NaloxoneAlphaprodine, 341

absolute configuration, 342analgesic activity, 341-342analogs, 345; see also Norprodineantipodes, SAR, 342, 346clinical use, 342

a.AlIylprodine, 343-344

543

544

conformation, 385nuclear magnetic resonance, 380-382stereochemistry, 385x-ray crystallography, 378

j1-Allylprodineconformation, 385nuclear magnetic resonance, 380-382stereochemistry. 385x-ray crystallography, 378

Aluminum(lIl), interaction with[Leu]enkephalin.531

Alvodine, see PiminodineAmidon(e), 4006-Amino-6-deoxymorphine. 66

(4' -Amino-Phe"]enkephaJin, fluorescencespectroscopy, 527

Amphetamine. 177Analgesia

choice of test, 36-375 receptor, and involvement, 36K receptor, and involvement, 36methods of measurement, 35-36J.Lreceptor, and involvement, 36opioid receptor sensitivity, 37opioid site of action, 36

AniJeridine, 324-3254-Anilinopiperidines, 362-367; see specific

compound, Fentanyl; see alw 4-Anilidopiperidines, Fentanyl, specificcompound

rigid analogs, 366-367SAR, 363-367synthesis, 362-363

Arylpiperidinesconformation, 378-394molecular modeling, 388-394nuclear magnetic resonance, 380-384physicochemical studies, 377-384QSAR, 394-398x-ray crystallography, 378-380

Azabicycloalkanes, 174Aza-des-N-morphinan

SAR, 236-238synthesis, 236-238

6-Azido-6-deoxycodeine, 656-Azido-6-deoxymorphine, 65Azidomorphine, x-ray crystallography,

167, 169

Index

B

Bemidone; see also Ketobemidoneanalgesic activity, 332analogs, SAR, 332analogs, synthesis, 331

Benzazepines, 306Benzazocines, 305-306Benzethidine, 325-326Benzimidazoles, 436-438Benzomorphans, 250-311

hetrocyclic A-ring substitutions, 296history, 250nitrogen positional isomers, 306-310nomenclature, 251numbering system, 251opiate receptor affinity, 271, 281-282rigid analogs, 305-306SAR

6-alkyl substitution, 259-261A-ring substitution, 259-261, 295-296BC-ring enlargements and contrac-

tions, 297-3046,ll-dialkyl enantiomers, 2656,ll-dialkyl substitution, 263-266, 268dialkyI substitution, 268-2696-hydroxy substitution, 294II-hydroxy substitution, 292-294II-methyl substitution, 261-262N-ether substitution, 288N-heterocyclicalkyl substitution, 285-

288N-substitution, 273-289

alkyl groups, 273-276cycJoalkyl, 279-285cyanoethyl group, 276unsaturated, 277-285

I-oxygen substitution, 289-292parent nucleus, 259-2616-phenyl-ll-alkyl substitution, 266-2686-phenyl substitution, 260, 263, 266-

268summary, 310-311trialkyl substitution, 269, 2846,1 1,1 I-trialkyl substitution, 270-271

stereochemistry, 254synthesis, 252-259

lip-alkyl derivatives, 255-256Bischler-Napieralski reaction, 197,257

Index

I

I

Diels-Alder reaction, 257Grewe cyclization, 252-254homolytic cyclization, 257hydratroponitrile route, 252II-hydroxy substitution, 292II-methyl derivatives, 261I-oxygenated derivatives, 289-290from 4-phenyl-pyridine-2-carboxylic

acid, 259stereochemistry of substituents, 254tetralone route, 252, 255, 2616,1 1,1 I-trialkyl derivatives, 270

Benzylisoquinolineselectrochemical oxidation, 204-206Pschorr reaction, 48reaction with one electron oxidants, 203TI(III) oxidation, 48

Bischler-Napieralski reaction, 197,257synthesis of benzazepines, 306

[4'-Br-Phe~J-[Leu]enkephalin, x-ray crys-tallography, 515

[4'-Br-Phe4]-[MetJenkephalin, X-rdy crys-tallography, 515

Bremazocine, 283relative affinity, for K receptor, 35

Buprenorphine, 139-140Butorphanol, 227

molecular modeling, 175N-Butyroyl-N'-cinnamylpiperazine, 444

c

Calcium, interaction with enkephalins, 5314-Carbalkoxy-4-arylpiperidines, 319-331;

see specific compound; see al.w Me-peridine, Normeperidine, Bemidone

structure-activity relationships, 321-327synthesis, 319-321

p-Casein, 460Casomorphine, SAR, 462p-Casomorphin, 460

derivatives, 476-477structures, 461

p-Chlornaltrexamine, 69-70Chlorocodide, 63,8-Chlorooxymorphamine,69Chlorpromazine, 177Ciramadol, 443Circular dichroism, 166

1

545

dynorphin, 528-530endorphins, 528-530enkephalins, 516-522, 525, 528, 531Gly-Gly-Phe, 528lipotropin, 528-530Tyf-Gly-Gly, 528

Clastic opiate receptor binding, 233, 304-305

CLIP, contained in proopiomelanocortin,463

Cluster analysis, of enkephalin conform-ers, 535

CND, see Codeine N-oxideCodeine

biology, 59biosynthesis, 10-12biotransformation

in animals, 13-19N-oxides, 14, 16, 20O-demethylation, 14, 17in Papaver, 20

de methylation, 527,8-epoxide,607-methoxy,84morphine precursor, 10-12N-oxide, metabolite, 14, 16, 20opium alkaloid, 2SAR

A-ring substitution, 79, 80C-7 substitution, 84-93C-8 substitution, 93

synthesis, 45-48, 51-52x-ray crystallography, 167-168

(+ )-Codeine, 56synthesis, 51

trans-Codiene, 57-58Codeinone

cuprate addition, 93morphine precursor, 10-12

Codorphone, 94Conformationally restricted analogs, of

enkephalins, 532Copper, interaction with enkephalins, 531Cyclazocine, 279

enantiomers, 280methyl ether, 281II-stereoisomers, 281

Cyclohexenylethyl amine, 197Cyclohexylamines, 438-441

546

cyclo-[Leu]enkephalin, nuclear magneticresonance, 521

cyclo-[MetJenkephalin. nuclear magneticresonance, 521

7,S-Cyc1opropylcodeinone. 62Cyclorphan, 217-218, 221

analog, 208Cymidon, see Ketobemidone

D

DADLE; .H'(' D-Ala1-D-Leu~-cnkephalinDAGO; H'(' Tyr-o-Ala-Gly-MePhe-Gly-olDALECK, 498DAME, opiate receptor affinities. 474DAMME, see FK33-824Demccol, see Meperidine3-Deoxymorphine, 58Dependence. drug,

definition, 39K receptor, and involvement, 40J.Lreceptor, and involvement, 40physical

animal model, 39definition, 39

psychicanimal model, 39-40correlation of animal model and clini-

cal experience, 40definition, 39

Demorphin. 460SAR, 462structure, 461

3-Desmethylnorprodine. analogsSAR, 338-341analgesic activity, 338, 340

3-Desmethylprodine, analogsSAR, 337-339N-I substitution, see 3-Desmethyl-

norprodinesynthesis, 335-337

Dextromethorphan, 207x-ray crystallography, 167, 169

Dextromoramide, 419, 453Dextrorphan, 2073,6-Diacetylmorphine, metabolism, 14, 18Diamorphine, see HeroinDiampromid, 428, 430-432

Index

Diazepam, 177lrans- 3 ,4-dichloro-N-methyl-N-(2-( I-pyrro-

lidinyl)-cyclohex ylJ-benzeneacetamideand analgesia, 36relative affinity, for K receptor, 35

3,6-Dideoxymorphine,58Diels-Alder reaction, synthesis of benzo-

morphans, 257Dihydrocodeine, 7,7-dimethyl, 89Dihydrocodeinone, 51, 60

chloromethylation, 807,7-dimethyl,89enol ether, 81reaction with DMF acetal, 87reductive cleavage to morphinans, 191

Dihydromorphine, 60QSAR, 184-185relative affinity, for 1J.receptor, 34

Dihydromorphinone, 63, 65metabolite, 14, 16metabolite, hydroxy, 16-17

Dihydrothebaine, Grignard reaction, 221-222

Dihydrothebainequinone, 114base-catalyzed rearrangement, 112-114

Dihydrothebainone, 514-hydroxyl removal, 211SAR,214-215synthesis, 48, 192synthesis from dihydrocodeinone, 191

13-Dimethyl-4-phenyl-4-propionyloxypiperi_dine, x-ray crystallography, 378

Dimethylpiperidinesconformation, 385-388nuclear magnetic resonance, 380-384stereochemistry, 385-388

,B,y-Dimyristoyl-Iecithin, see PhospholipidDionin, 59Diphenylethylpiperazines, 441-442Diphenylhydantoin, 177Diprenorphine, 139-140Dissociation constant, 166, 173

of enkephalins, 525, 534Dolantin, see MeperidineDPE~, .\'i'l' ITyr-o-Afa-Gly-Phc-

LeuNIIJ,-iCII,hDSLET, .\'i'l' Tyr-o-Scr-Gly-Phe-Lcu-ThrDTEt:, ,\'l'l' ITyr-o-Ala-Gly-

PhcNHh'(cH~)t:

Index

DTLET, ,\'i'l' Tyr-o-Thr-Gly-Phc-Leu_ThrDynorphin

biology, 470circular dichroism, 528-530fluorescence spectroscopy, 530nuclear magnetic resonance, 528-529opiate receptor affinities, 470structure, 461

Dynorphinl_9, relative affinity, for K recep-tor, 35

E

Electrochemical oxidation of I-benzyliso-quinolines, 204-206

Empirical conformational energy of pep-tides and proteins (ECEPP), 533-534

6,14-Endoethenotetrahydrothebaine, 110;see also Thebaine, Diels-Alder ad-ducts

C-19 alcohols, see Thevinols, OrvinolsEndorphins, 460

circular dichroism, 528-530contained in proopiomelanocorlin, 463-

465nuclear magnetic resonance, 528-529structures, 461ultraviolet spectroscopy, 529-530

f3-Endorphinbiology, 465effect, respiration, 37opiate receptor affinities, 465, 468SAR, 465

Enkephalins, 459-512, 513-537biology, 466clinicaJIy investigated, 500-502comparison with rigid opiates, 475conformation, 513-537cyclic derivatives, 477deuterium labeled, 516, 519, 523, 525,

528dimeric, 481dipeptide derivatives, 481dissociation constants, 525fluorescence spectroscopy, 527, 534-535history, 459infrared spectroscopy, 516laser Raman spectroscopy, 515-516, 518metal ion interactions, 531

1

547

molecular modeling, 532-537nuclear magnetic resonance, 516-531occurrence in adrenal glands, 466opiate receptor affinities, 466opiate receptof affinities summary, 503opiate recept6r selectivities, 473-4815-opiate receptor selectivity SAR, 479p.-opiate receptor selectivity SAR, 475opioid antagonists, 499opioid antagonist isosteres, 499

penicillamine-containing, 480QSAR, 537

SAR,481-499C-terminus, 499Leu~ replacement by dehydro-Leu,

498Met~/Leu~, 4%-499Met~/Leu~ backbone alkylation, 499Met~/Leu~ replacements, 497Met5/Leus rigid analogs, 499minimum chain length for analgesia,

481N-terminus, 482N-terminus amino acid additions, 484Phe~ backbone alkylation, 494Phe~ replacement by dehydro-Phe,

492Phe~ reduction to hexahydro, 494Phe~ rigid analogs, 495Phe4 substituents, 492Phe4 substituted, 493Summary, 502tyrosine N-substitutions, 483tyrosine replacement, 483-485x-ray crystallography, 514-515

Enkephalinamides, metal ion interactions,531

Eptazocine, 303EseroJine, 182Ethoheptazine, 329-330Ethylketocyclazocine, 290

and analgesia, 36opiate receptor affinity, 291relative affinity, for K receptorII-stereoisomer, 290

Ethyl l-methyl-4-phenylpiperidine_4_car_boxylate, see Meperidine

Ethylthevinoate, 105Etonitazine, 174

548

Etorphineanalgesic activity. 132benzoylthio, 133clinical use, 133QSAR, 184-185receptor binding, 133relative affinity, for jJ. receptor, 34x-ray crystallography, 153

S-Etorphine, 133Etoxeridine. 325-326

F

FAO, 117-118Fentanyl

absolute configuration, 367analgesic activity, 363-364analogs, 365-366clinical use, 365isothiocyanates, 365, 367molecular modeling, 174QSAR, 184-185,397-398

Flavothebaone. 114Fluorescence spectroscopy

(4'.amino-Phe(]enkephalin, 527dynorphin, 530[Leu]enkephalin, 527[Mel]enkephalin, 527, 534[Ser']enkephalin, 528[Trp']enkephalins, 527-528, 535Tyr-Met-Gly-Trp-Pro.522Tyr-Met-Gly-Trp-Pro-NHh 527Tyr-Pro-Gly-Phe-Leu, 522Tyr-Pro-Gly-Phe-Met, 522

FK-33-824, 34, 477clinical investigations. 500

Fremy's salt oxidations, 213,B-Funaltrexamine, 71

antagonism, respiratory depression, byopioids, 38

2-(2-Furyl)ethyl levorphanol, QSAR, 184-185

G

Gastrointestinal motilityI( receptor, and involvement, 38J.Lreceptor, and involvement, 38opioid site of action, 38

Index Index

Gemazocine, 270Gly-Gly-Phe, circular dichroism, 528Gly-Gly-Phe-Leu

nuclear magnetic resonance, 518x-ray crystallography, 515

Gly-Gly-Phe-Met, nuclear magnetic reso-nance, 518

Glyol, see DAGOGly-Tyr-Gly-Gly-Phe-Met, nuclear mag-

netic resonance, 520GPA-1657,266-267Grewe reaction

by-products, 197-199catalysts, 196effects of N-substituents, 196regiochemistry, 1%stereochemistry of, 197synthesis of benzomorphans, 252-254synthesis of 14-hydroxymorphinans, 201synthesis of morphinans, 193-199

Imipramine, 177Infrared spectroscopy, 166

[Leu]enkephalin, 516, 519-520, 525-526

[Met]enkephalio, 519-520, 525-526Isofentanyl, 364IsomethadoJ, 411-414

infrared spectroscopy, 452nuclear magnetic resonance, 452synthesis, 411

Isomethadoneacyloxy analogs, 424amide analogs, 416, 418conformation, 448-451dissociation constant, 448-449ether analogs, 424imine derivatives, 422molecular modeling, 457nuclear magnetic resonance, 449-450stereoisomers, 401, 404-405, 408-409synthesis, 401, 403x-ray crystallography, 451

IsomorphinanSAR, 208-209

C-6 substitution, 212C-7 substitution, 221-225C-14 hydroxyl substitution, 228-229

synthesis, 197Isoneopine, 56Isonepenthone, 112-113Isopethidine, 322Isoprodine, 342Isopromedol, stereoisomers

SAR, 348, 350synthesis, 347

H

(+)-Heroin,56Heroin, see also 3,6-Diacetylmorphine

7,8-epoxide,61history, 55SAR, 59

Homobenzomorphans, 299-303Hydrocodeinone hydrazone, oxidative

cleavage to morphinans, 191Hydrocodone, 14

hydroxy metabolites, 17Hydromorphone, !iee also Dihydromorphi-

noneQSAR, 184-185

Hydroxyazidomorphine, x-ray crystallogra-phy, 167

14-Hydroxycodeinone, see oxycodone3-Hydroxylevallorphan, x-ray crystallogra-

phy, 167, 169

14-HydroxyisomorphinanSAR, 228synthesis, 229

14-Hydroxymorphinans, synthesis, 199-201

(3-Hydroxyphenyl)methylmorphans, 360-361

K

Ketobemidoneanalgesic activity, 333analogs, SAR, 332-334clinical use, 333molecular modeling, 388QSAR, 184-185synthesis, 331

Ketocyclazocine, 290effect, in chronic spinal dog, 31

549

opiate receptor affinity, 291relative affinity, for I( receptor, 35

6-Keto-morphinans, 213-215reduction to alcohols, 214SAR

C-7 substitution, 221-22514-hydroxy substitution, 229-230N-substitution, 218

4-Ketoxy-4-arylpiperidines, 331-334; seealso Ketobemidone

SAR, 332-334synthesis, 33 t ~

Kyotorphin, 460structure, 461

L

Laser Raman spectroscopy[Leu]enkepha1in, 515, 518, 525-526[Mellenkephalin, 519-520, 525-526

Laudanine, morphine precursor, 7-8Laudanosine, oxidation, 206Leptanal, see FentanylLeritine, see Anileridine[Leu]enkephalin

aluminum interaction, 531carbon-13 labeled, 518conformation, 513-537deuterium labeled, 516, 519, 525effect, in guinea pig ileum, 31effect, in mouse vas deferens, 31fluorescence spectroscopy, 527-528infrared spectroscopy, 516, 519-520,

525-526ionization state, 518, 525laser Raman spectroscopy, 515, 518-

520, 525-526Monte Carlo simulation, 534-535nitrogen-15 labeled, 518-519, 523nuclear magnetic resonance, 516, 518-

519,522-523,525,528,531occurrence in prodynorphin, 470occurrence in proenkephalin, 466opiate receptor affinities, 468opiate receptor selectivities, 474structure, 461x-ray crystallography, 514-515

Levallorphan, 216-217, 221Levomethorphan, 207, 211

550

LevorphanolQSAR, 184-185relative affinity, for 1J.receptor, 34

Lipotropincircular dichroism, 528-530nuclear magnetic resonance, 528-529

p- LipotrOf)in, 463Lonan, see LevallorphanLY-t27,623, see MetkephamidLysergic acid diethylamide (LSD), 177Lysophosphatidyl glycerol. see Phospho-

lipidLys- Tyr-Gly-Gly-Phe-Met, nuclear mag-

netic resonance, 520

M

6-MAM, see 6-0-monoacetylmorphineManganese, interaction with enkephalins,

531Meperidine

analgesic activity, 325analogs, see also Bemidone

C-4 acyloxy, see 4-Acyloxy-4-arylpj-peridines, Prodine

C-4 alkyl. see 4-Alkyl-4-arylpiperi-dines

C-4 anilino. see 4-Anilinopiperidines.Fentanyl

azacycloheptane, 328-330C-4 hydroxy, see 4-Phenyl-4-piperi-

dinolsC-4 ketoxy, see 4-Ketoxy-4-arylpiperi-

dines, KetobemidoneN-I substitution, see Normeperidine

C-4 aryl, SAR, 322-325C-4 carbalkoxy, SAR, 322-325clinical use, 323-324, 328conformation, 385, 388-394molecular modeling, 388-394synthesis, 319-321x-ray crystallography, 378

p-Meprodine, 343-344Meptazinol, 356MES, see Morphine-3-sulfateMetal ions, interactions with enkephalins,

531Metamorphinan, 235Metazocine, 265

Index Index

enantiomers, 265racemate, 264

[Met]enkephalincarbon-13 labeled, 526circular dichroism, 528conformation, 513-537deuterium labeled, 523, 528dissociation constants, 525effect

in guinea pig ileum, 31in mouse vas deferens, 31respiration, 37

fluorescence spectroscopy, 527infrared spectroscopy, 519-520, 525-526ionization state, 525laser Raman spectroscopy, 519-520,

525-526nuclear magnetic resonance, 516-517,

519-520,523-528,530-531OCCUITencein proenkephalin, 466OCCUITencein proopiomelanocortin, 465opiate receptor affinities, 468opiate receptor selectivities, 474structure, 461x-ray crystallography, 515

[Met]enkephalinamide, nuclear magneticresonance, 519

[Met]enkephalin-Arg6-Gly'-Leu8, 460-461[MetJenkephalin-Arg6_Phe', 460-461Melanocyte stimulating hormone, con-

tained in proopiomelanocortin, 463Methadol,411-414

conformation, 451-453dissociation constant, 452infrared spectroscopy, 451-452nuclear magnetic resonance, 452receptor binding, 414stereoisomers, 411-412synthesis, 411x-ray crystallography, 453

Methadoneactivity, 400conformation, 448-451discovery, 400dissociation constant, 448-449, 451metabolism, 404metabolite, 405molecular modeling, 456-457nuclear magnetic resonance, 449-450QSAR,184-185

receptor binding, 404, 414stereoisomers, 401, 403-405, 408-409structure-activity relationships, 406-435

alkylamine modifications, 406-411amide analogs, 416-419diphenyl modifications, 425-435ester analogs, 415-416imine derivatives, 421-423ketone modifications, 411-425phosphorus analogs, 419-421sulfur analogs, 419, 421-422

toxicity, 404x-ray crystallography, 451Methadone-N-oxide, 4055-Methyldihydrocodeinone,825-Methyldihydromorphinone, ~'ee Metopon3-Metbylfentanyl, QSAR, 397-3983-Methylfentanylisothiocyanate, 365, 3675-Methylmethadone

conformation, 450dissociation constant, 450-451molecular modeling, 457nuclear magnetic resonance, 450stereoisomers, 409-411synthesis, 410x-ray crystallography, 451

N-Methylmorphine, 74N-Methylnalorphine, x-ray crystallogra-

phy, 167Methylpiperidines

conformation, 385nuclear magnetic resonance, 381stereochemistry, 385x-ray crystallography, 378

Metkephamidclinical investigations, 500SAR, 493

Metopon, 81-836-aJcohol, 83

[Me-Trp4,Met5Jenkephalin, Monte Carlosimulation, 535

MNO, see Morphine N-oxideMolecular mechanics, see Molecular mod-

elingMolecular modeling

[Ala2,Met5]enkephalin, 534lo-Ala~,Mct~lcnkephalin, 534azabicycloaJkanes, 174benzomorphans, 176-179butorphanol, 175

551

dimethylpiperidines, 390

enkephalins, 532-537

fentanyl, 176

isomethadone, 457

y-isopromedol, 390

ketobemidone, 388

meperidine, 388-394

methadone, 456-457

5-methylmethadone, 457morphinans, 175-176

morphine, 174-183

nalorphine, 177-179

naloxone, 175

naltrexone. 175oripavine derivatives, 182-183

4-phenylpiperidines, 174,.-t76, 388-394

prodines. 388-394

a-promedol, 390

Tyr-cyclo[N-y-Dbu-Gly-Phe_Leu], 5336-0-Monoacetylmorphine, 14, 18Monte Carlo simulation

[Ala2,Trp4,Met5]enkephalin, 535[D-Ala2,Trp4,Met~]enkephalin, 535(Leu]enkephalin, 534-535

[Me-Trp4,Met~]enkephalin. 535[Trp4]enkephalins, 535[Trp"Me-Leu~]enkephalin, 535[Trp4,Met~Jenkephalin, 535

Tyr-Ala-Gly-Phe, 535

Tyr-Gly-Gly-Phe, 535

Morpheridine, 325-326

Morphiceptin, 476

relative affinity, for 1J. receptor, 34

Morphinans

molecular modeling, 175-176

naturally occurring, 189opiate receptor affinities, 220-221

SAR, 206-241

annulated derivatives, 231

A-ring reduction, 210

A-ring substitution, 220, 240

9-Aza derivatives, 239

C-7,8 disubstitution, 227

C-IO-homo derivatives, 234

C-14 hydroxyl substitution, 227-230

C-nor derivatives, 232

C-IO oxygen substitution, 227

C-3 substitution, 209-210C-6 substitution, 210-215, 218, 221-

225, 229-230

552

C.7 substitution, 221-225C-8 substitution, 224-226Diels-Alder adducts, 230-231D-nor derivatives, 232enantiomers, 207-208isomorphinans, 208-2095-methyl substitution, 220-221N-heterocyclic alkyl substitution, 218-

219nitrogen substitution, 215-220, 223-

230oxa derivatives, 240-241

synthesisannulated derivatives, 2319-Aza derivatives, 239from, I-benzyIisoquinolines, 201-204C/D nor and homo derivatives. 232-

235by electrochemical oxidation, 204-206Grewe cyclization, 193-19914-hydroxy derivatives, 199-201isomorphinan by-products, 197from, morphine anaJogs, 190-193by, one electron oxidants, 203

oxa-derivatives, 240-241by, PschoIT reaction, 201[otal, 193-206

Morphinandienones. synthesis, 201-207Morphine

3-acetyl, 596-acetyl, 59biosynthesis, 7-13

from tyrosine, 8-9biotransformation, 13-20

in animals, 13-19in Papaver, 19-20conjugation, 13-15glucuronide formation, 14-15sulfate formation, 14-15N-demethylation, 14-16N-oxidation, 14, 16O-methylation, 14, 16-17route of administration, 22-24

bond polarities, 180-183charge densities, 180-183chromium complex, 94disposition, 20-24

three-compartment model, 21effect

in chronic spinal dog, 31

IndexIndex

in guinea pig ileum, 31in mouse vas deferens, 31respimtion. C02 stimulus-response

curve, man, 37electrostatic potentials, 180-183elimination

from plasma, 20-22in urine, 21-22

history, 2isolated

from bovine brain, 30from frog skin, 30

to-methyl. 95nuclear magnetic resonance, 170, 172QSAR, 184-185relative affinity, for J.Lreceptor, 34SAR,55-101

A-ring substitution, 79C-3 substitution. 58-60C-5 substitution, 81-84C-6 substitution, 62-72C-7 substitution, 84-93C.8 substitution, 93C-IO substitution, 94C-14 substitution. 95-1013,6-diesters, 593-ethers, 59history, 55N-substitution, 72-79summary, 155

structure, 45synthesis, 45-55

aryJpiperidine route. 52-53biomimetic, 48-49from codeine, 52Gates, 45-48Grewe, 48Rice, 51-52

x-my crystallography, 167-168, 173(+)-Morphine,56

synthesis, 51trans-Morphine, 56-68

SAR, 58synthesis, 57

Morphine 7,8-epoxide, 60-61Morphine-3-glucuronide, 14-15 .Morphine N-oxide, metabolite, 14, 16, 20,

74Morphine.3-sulfate, 14-15Morphinone, 63

Moxazocine, 294

MR-2034, 286-288

opiate receptor affinities, 288

MTD, see Steric mapping

N

Nalbuphine, 78effect, respiration, C02 stimulus-re_

sponse curve, man. 37x-ray crystallography, 167, 169

Nalmexone, 77Nalorphine. 76

molecular modeling, 177-179x-ray crystalJography, 167-168

Naloxonazine, antagonism, respiratorydepression, by opioids, 38

Naloxone, 18-19.76-77hydroxy metabolites, 18-19molecular modeling, 175x-ray crystallography, 167-168

(+)-Naloxone,77Naltrexol. 78

nuclear magnetic resonance, 170-171Naltrexone, 18-19,78

hydroxy metabolites, 18-19molecular modeling, 175

Neoendorphins, 460biology, 470opiate receptor affinities, 470structures, 461

Neopine, nuclear magnetic resonance,170

Neopinone, morphine precursor, 10-12Nepenthone, lOS, 112-113Nisentil, see AlphaprodineNorbenzomorphans, 298Norcodeine, N-allyl, 75Norheroin. 73-74

metabolite, 14, 18Nor-homobenzomorphans, 303Norlaudanosoline

I-carboxylic acid, 8-9dimethyl ether, 9-10morphine precursor, 8-10

Normeperidineanalgesic activity, 324-325analogs

clinical use, 325. 328

553

SAR, 324-327synthesis, 321

synthesis. 321N ormethadol

infrared spectroscopy, 451opticaJ rotatory dispersion, 453stereoisomers, 453

Normethadone, 408-409acyloxy analogs, 424amide analogs, 416-417nuclear magnetic resonance, 449x.ray crystallography, 451

Normorphine6-acetyl, 73N-alkyl substitution, 75-76biology, 73metabolite, 14-15QSAR, 184-185synthesis, 72

Norprodine. analogs, SAR, 345-346Nuclear magnetic resonance, 166

a-allylprodine, 380-382jJ-allylprodine, 380-382arylpiperidines. 378-380cyclo-fLeu]enkephalin, 521cyclo-[MetJenkephalin, 521dimethylpiperidines, 380-384dynorphin, 528-529endorphins. 528-529enkephalins, 516-531Gly-Gly-Phe-Leu,518Gly-Gly-Phe-Met,518Gly-Tyr-Gly-Gly-Phe-Me[, 520isomethadone, 449-450[Leu]enkephalin, 516, 518-519, 522-523,

525,528,531lipotropin. 528-529Lys-Tyr-Gly-Gly-Phe-Met, 520[Met]enkephalin, 516-517, 519-520,

523-528, 530-531fMet]enkephalinamide, 519methadone, 449-4505-methylmethadone, 450morphine, 170, 172naltrexol, 170-171neopine, 170normethadone, 4494-phenylpiperidines, 380-384Phe-Tyr-Gly-GIY-Phe-Met, 520a-prodine, 380-382

554

{3-prodine, 380-382

a.prodine alcohol, 380-382

,B-prodine alcohol, 380-382

thebaine, 170

1,2,6-trimethyl-4-phenyl-4-acetoxypiperi_dine, 380-382

(t- J ,2.3-trimethyl-4-phenyl-4-piperidinol,

380-382, 384

[3-t,2,3-trimethyl-4-phenyl-4-piperidinol,380-382, 384

y-I ,2,3-trimethyl-4-phenyl-4-piperidinol.

380-382, 384

a-I,2,5-trimethyl-4-phenyl-4-piperidinol,380-382, 384

{3-t,2,5-trimethyl-4-phenyl-4-piperidinol,380-382, 384

y-l,2,5-trimethyJ-4-phenyl-4-piperidinol.380-382, 384

5-1 ,2,5-trimethyl-4-phenyl-4-piperidinol,

380-382

a-I,2,3-trimethyl-4-phenyl-4-propiony_loxypiperidine, 380-382

{3-1,2,3-trimethyl-4-phenyI-4-propiony_loxypiperidine, 380-382

y-I,2,3-trimethyl-4-phenyl-4-propiony_loxypiperidine, 380-382

trimethylpiperidines, 380-384Tyr-o-Ala-Gly-Phe-Met, 521-523

Tyr-D-Ala-Gly-Phe-Nva, 522

Tyr-cyc/o[N-e-Lys-Gly-Phe_LeuJ, 532Tyr-cyc/o[N-S-Orn-Gly-Phe_Leu), 532-

533


Tyr-Met-Gly-Phe-Prn, 521, 523

Tyr-Tyr-GIY-Gly-Phe_Met, 520

o

Operidine, see PhenoperidineOpiate analgesics, production quotas, 6Opiate receptor

~in rat vas deferens, 32prototypic ligand, 33

initial discovery, 29K

distribution in central nervous system,36-37

effect of activation, in chronic spinaldog, 31

Index Index

in rabbit vas deferens, 32prototypic ligand, 31, 33 P

P-effect of activation in chronic spinal

dog, 31in guinea pig ileum, 32prototypic ligand, 31, 33

multiplicity, 31-35biochemical characterization, 32-34pharmacologic characterization, 31-32

probes, 67-72selective protection, 32

pA2, definition, 32

Pallidine, biomimetic synthesis, 203

Partition coefficient, 166, 173

Pattern recognition, 183

PCILD calculations

benzomorphans, 176-181, 183

dimethylpiperidines, 390fentanyl, 176

y-isopromedol, 390

morphinans, 176

morphine, 176

nalorphine, 177-179

oripavine derivatives, 182-183

4-phenylpiperidines, 176,390-394

a-prodine, 390-394

/J-prodine, 390-394

a-promedol, 390

[D-Pen2,o-Cys~J-enkephalin, relative affin-ity, for () receptor, 35

ID-Pen2 ,D-Cysl]-cnkephalinamide, rchlliveaffinity, for () receplor, 35

1[)-Pen2,L-Cys~]-enkephalin. relative affin-ity. for S receptor, 35

ID-Pen2,L-Cysl]-enkephalinamide, relativeaffinity. for S receptor, 35

ID-Pen2.o-Penl]-enkcphalin. relative affin-ity, for S receplor. 35

[D-Pen2,L-Pen~J-enkepharin. relative affin-ity. for S receptor, 35

Pentazocine, 278-279

effect, respiration, C02 stimulus-re-

sponse curve, man, 37

enantiomers, 280

ll-stereoisomers, 280

Peptide E, 461

Peptide synthesis, 471-473

solid phase methods, 472

solution methods, 471PET, 130, 153

Pethidine, see MeperidineQSAR, 184-185

PH-8P,460

structure, 461

Phenampromid, 428-430

Phenazocine, 277

relative affinity, for J.Lreceptor, 34

Phenethyl thebaine, 130, 153

Phenobarbital, 177

" elTect of activation. in chronic spinaldog, 31

prototypic ligand, 31, 33Dpioid, biological effects, summary, 30Opioid peptides, 459-470

biosynthesis, 463-470from adrenal glands, 466history, 459-470types, 460

Opium, 1-5alkaloids, 2economics, 5history, Iproduction, 5

Optical rotatory dispersion, 166Oripavine

biosynthesis, 12derivatives of, PCILO calculations, 182-

183Orvinols; see also specific compound

acid-catalyzed rearrangement, 140-147acetylation at C-3, 132-133analgesic activity, 131-132, 134N-substitution, SAR, 137-138

3-deoxy, 1396,14-endoethano, 139-140

Oxilorphan, 227-228Oxycodone, %-97; see also Oxy-

morphone, azinebiology, 97conversion to oxymorphone, 97ester SAR, 97-99

Oxymorphone, 66, 69, 76azine, 66biology, 97hydrazone, 66x-ray crystallography, 167-168

555

Phenoperidine, 325-326I-Phenyl-3-aminotetralins, QSAR, 183-

1844-Phenyl-4-piperidinols

synthesis, 336-337SAR,339

6-PhenylbenzomorphansSAR

261, 263, 266-268N-substitution, 277, 281

synthesis, 260-262, 266-2674-Phenylpiperidines

conformation, 378-394molecular modeling, 388-394nuclear magnetic resonance, 380-384PCILO calculations, 176physicochemical studies, 377-384 /QSAR, 392-398x-ray crystallography, 378-380

4-Phenylpiperidine-2-carboxylic acids, usein benzomorphan synthesis, 260

Phe-Tyr-Gly-Gly-Phe-Met, nuclear mag-netic resonance, 520

Phosphatidylserine, .\'ee PhospholipidPhospholipid

interaction with dynorphin. 530interaction with {Met]enkephalin, 530-

531Piminodine, 325Piperdones, use in benzomorphan synthe-

sis,270POMC, see ProopiomelanocortinPotassium, interaction with enkephalins,

531Prodine; see also 3-Desmethylprodine,

specific compoundanalgesic activity, 341-342, 346analogs

C-3 alkylation; see also a-Prodine, {3-Prodine

C-3 alkylation, isomers, SAR, 341-346

configuration, 341-342, 346N-I substitution, see Norprodinering-contraction, SAR, 351-352; Jee

also Prodilidenering.expanded, SAR. 351

a.Prodineconformation, 385, 388-394molecular modeling, 388-394

556

nuclear magnetic resonance, 380-382

stereochemistry, 385x-ray crystallography, 378

,B-Prodine, 341absolute configuration, 342analgesic activity, 341-342analogs, 345; see also Norprodineantipodes. SAR, 342conformation, 385. 388-394molecular modeling, 388-394nuclear magnetic resonance, 380-382stereochemistry, 385x-ray crystallography. 378

a-Prodine alcohol, nuclear magnetic reso-nance, 380-382

J3-Prodine alcohol, nuclear magnetic reso-nance, 380-382

Prodynorphin, 468-470structure, 469

Profado!, 356-357Proenkephalin. 465-468

structure. 467Proenkephalin 8, see ProdynorphinPromedol, see also 1,2,5-Trimelhyl_4_

phenyl-4-piperidinoJstereoisomers, SAR, 349-351synthesis, 347

Proopiocortin, see ProopiomelanocortinProopiomelanocortin, 463

biosynthesis, 465processing, 465structure, 464

Propiram,432-435,454_455Propoxyphene, 427-428, 453-454N-Propylnormorphine, antagonist proper-

ties, 75J9-Propylthevinol

nuclear magnetic resonance, 172x-ray crystallography, 167, 169

Proton affinity, 176, 183Proxorphan, 240Pyridinium salts

Grignard addition, 253, 256use in benzomorphan synthesis, 253,

256, 2595a,7a,8{3.( - )-N-[7-(I-PyrrolidinYI)-I_oxas_

piro[4,5]dec.8-yIJbenzeneacetamide,relative affinity, for K receptor, 35

Index Index

Qs

Quantitative structure-activity relation-ships (QSAR), 183-185

dihydromorphine, 184-185enkephalins, 537etorphine, 184-185fentanyl, 184-1852.(2-furyl)ethyJ levorphanol, 184-185hydromorphone, 184-185ketobemidone, 184-185levorphanol, 184-185methadone, 184-1853-methylfentanyl analogs, 397-398morphine, 184-185normorphine, 184-185l-phenyl-3.aminotetralins, 183-1844-phenylpiperidines, 392-398

Quasi.morphine withdrawal syndrome, 306Quaterary morphine salts, 74-75

Salutaridinebiomimetic synthesis, 203morphine precursor, 8, 10-11occurrence, 189opium alkaloid, 2synthesis, 48, 192

Salutaridinoll, morphine precursor, 10-11SD-25, see SyndyphaJin[Ser2,LeujJenkephalin, fluorescence spec-

troscopy, 527-528Sinomenine, conversion to (+)-morphine,

189Sinomeninone, 85SKF-10047, see N-AllylnormetazocineSodium, interaction with enkephalins, 531Steric mapping, 184-185Sublimase, see FentanylSufentanil, 365Syndyphalin, 477

R

Racemethorphan, 207Receptor binding

acetylmethadol,414N,N.dinoracetylmethadoJ, 414N,N-dinormethadol,414methadol,414methadone, 414N-noracetylmethadol,414N-normethadol, 414propoxyphene, 428

Respiration, method of measurement, 37Respiratory depression

by opioids, 37-38{j receptor, and involvement, 38J.Lreceptor, and involvement, 38

Reticulinemorphine precursor, 9-11oxidation, 206

Reversed esters of meperidine, 334-352;see al.\'O4.Acyloxy-4-arylpiperidines,Prodine, specific compound

RevivonR, see DiprenorphineRimorphin, 468

bioJogy, 470opiate receptor affinities, 470structure, 461

T

TengesicR, see BuprenorphineTetrahydropyridines, use in benzomorphan

synthesis, 253, 256Thebaine, 81

air oxidation, 193Birch reduction, 193,212bromination, 1926-demethoxy-, /11-112Diels-Alder adducts, 101-153; see also

specific compound7-alkyl, analgesia, 1157-alkyl, synthesis, 114-1157-amino, 117-11914-arylamino, analgesia, 108base-catalyzed rearrangement, 112-

113,121-122C-7 derivatives, 126-127C-7 substitution, 103-107C-14 substitution, 106-108chemical anatomy, 156-157O-demethylation, 108-1117,8.disubstitution, synthesis, analgesic

activity, 1227,8-disubstitution, synthesis, from

ethyJenes, 118-120

557

7,8-disubstitution, synthesis, frommaleic anhydride, 120-121

general structure, 1027-keto, analgesia, 1067-keto, conversion to alcohols, 128-

129; see also Thevinols7-keto, narcotic antagonism, 1367-methylfumaramido, receptor probe,

117-118opiate receptor probes, 153-1547-oxo, analgesia, 110-1117-oxo, conversion to 7{3-alcohol, 149-

150peptide derivatives, 115-117

stereochemistry, assignment, 103-105,118-120

stereochemistry, physical methodol.ogy, 124-126

7-sulfone, analgesia, 107synthesis, acetylene dienophiles, 123synthesis, aromatic nitroso

dienophiles, 106-108synthesis, ethylene dienophiles, 103-

107, 118-120fJ-dihydro-, 111-112from Papaver brae/ea/urn, 5, 7hydride reduction, 193morphine precursor, 8, 10-12nuclear magnetic resonance, 170opium alkaloid, 2organocuprate addition, 221-222oxidation

by hydrogen peroxide, 95by peracids, 95

reaction with cuprates, 86reaction with N204, 98rearrangement to metathebainone, 235-

236synthesis, 48

Thevinoic acid, 116Thevinols

A-ring derivatization, 147-148acid.catalyzed rearrangement, 140-147C-19 configuration, 128-1297{3-diastereoisomers, 149-15015,16-modification, 147-148

16-alkyl, 149N-substitution

synthesis, 135-136

558

SAR, 136-137O-demethylation, 131-132

at C-3, see Oevinolsreduction to 6,14.endoethano, 134stereochemistry

physical methodology, 150-153x-ray crystallography, 153

synthesis from thevinone, 128-129Thevinone, 105, 112-113Thiambutene, 436-437, 455Tilidine, 439Trimeperidine, see Promedol

..1,2.6- Trimethyl-4-phenyl-4-acetoxyplpen-dine

conformation, 387nuclear magnetic resonance, 380-382stereochemistry, 387x-ray crystallography, 378

1,2,5- Trimethyl-4-phenylpiperidines, no-menclature, 378

a-I ,2,3- Trimethyl-4-phenyl-4-piperidinolconformation, 385-386nuclear magnetic resonance, 380-382,

384stereochemistry, 385-386x-ray crystallography. 378

. ..{3-1,2,3- Trimethyl-4-phenyl-4-plpendlnolconfonnation, 385-386nuclear magnetic resonance, 380-382,

384stereochemistry, 385-386x-ray crystallography, 378

y-J 23-Trimethyl-4-phenyl-4-piperidinolc~~fonnation, 385-386nuclear magnetic resonance, 380-382,

384stereochemistry, 385-386x-ray crystallography, 378

a-I,2,5- Trimethyl-4-phenyl-4-piperidinolconformation, 386nuclear magnetic resonance, 380-382,

384stereochemistry, 386x-ray crystallography. 378

{3-I,2,5- Trimethyl-4-phenyl-4-piperidinolconformation, 386nuclear magnetic resonance, 380-382,

384stereochemistry, 386

y- J ,2,5- Trimethyl-4-phenyl-4-piperidinol

IndexIndex

conformation, 386nuclear magnetic resonance, 380-382.

384stereochemistry, 386x-ray crystallography. 378

5-1 ,2,5- Trimethyl-4-phenyl-4-piperidinolconformation. 386nuclear magnetic resonance, 380-382stereochemistry, 386

a-I,2 ,3-Trimethyl-4-phenyl-4-propionyloxy_piperidine. nuclear magnetic reso-nance, 380-382

{3-1,2,3- Trimethyl-4-phenyl-4-propionyloxy_piperidine, nuclear magnetic reso-nance, 380-382

y-I ,2,3- Trimethyl-4-phenyl-4-propionyloxy-piperidine, nuclear magnetic reso-nance, 380-382

')'-1,3,5- Trimethyl-4-phenyl-4-propionyloxy-piperidine

conformation, 387stereochemistry. 387x-ray crystallography, 378

Trimethyl-4-phenylpiperidines, nuclearmagnetic resonance, 380-384

[Trp4]enkephalinsfluorescence spectroscopy, 527, 535Monte Carlo simulation, 535

[Trp4,Me-Leu")enkephalin, Monte Carlosimulation, 535

[Trp\Met")enkephalin, Monte Carlo simu-lation, 535

Tyr-Ala-Gly-Phe, Monte Carlo simulation,535

Tyr-cyclo[N-y-Dbu-Gly-Phe-Leu], 533Tyr-cyclo[N-S-Om-Gly-Phe-Leu], 532-533Tyr-cyclo[N-B-Lys-Gly-Phe-LeuJ. 532-533

Tyr-o-Ala-Gly-MePhc-Gly-ol, relativeaffinity, for 1J-receptor. 34; ,W>('al.mDAGO. 477

Tyr-D-Ala-Gly-MePhe-Me(O).ol. .\'('(' FK-33-824

Tyr-D-Ala-Gly-MePhe-Met-(O).l)I. relativeaffinity. for 1J-receptor. 34

Tyr-D-Ala.Gly-Phe, Monte Carlo simula-tion, 535

Tyr-D-Ala-Gly.Phe-D-Leu, see DADLE[Tyr-D-Ala-Gly-Phe-LeuNHh'(CHh, rela-

tive affinity, for 5 receptor. 34

Tyr-n-AIa-Gly.Phe-(Me)"-lct_NH!. s('('mctkephamid. 493

Tyr-o-Ala-Gly-Phe_Met. nuclear magneticresonance. 5~ 1-523

[Tyr-D-Ala-UIY-PhcNHh'(CH:.),~, relativeaffinily. for 0 receptor. 34

Tyr-n-Ala-Gly-PhC-Nva. nuclear magneticresonance. 522

Tyr-D-Cys-Gly-Phe_Cys. 47X. 4XOTyr-D-Cys-Gly-Phe_n_Cys. 478. 4XOTyr-n-Met-Gly-Phe-Pro_NH~. clinical

investigations. 500

Tyr-D-Mct(O)-Gly-MePhe_ol. ,\'('(' Syn-dyphalin

l'yr-n-IJen-Gly_Phc_Pcn. 480Tyr-n-Pen-Gly-Phe_D_Pen, 480Tyr-n-Ser-Gly-Phe-Leu_Thr. relative affin-

ity. for 0 receptor. 34

Tyr-D-Thr-Gly-Phe-Leu_Thr, relaliveaffinity. for 8 receptor, 34: .I't'(' (/1.\'0

DTLETTyr.Gly-Gly. circular dichroism. 528

Tyr-Gly-Gly-Phe

Monte Carlo simulation, 535

nuclear magnetic resonance, 518

x-ray crystallography, 515Tyr-GIY-Gly-Phe-Leu, see [LeuJenkepha_

lin, enkephalins

Tyr.Gly-Gly.Phe-Met, see {MetJenkephalinTyr.Met.Gly-Phe-Pro, nuclear magnetic

resonance, 521, 523Tyr-Met-Gly-Trp_Pro, fluorescence spec-

troscopy, 522, 527

Tyr-Pro-Gly-Phe-Leu, fluorescence spec.troscopy, 522

Tyr-Pro-GJy-Phe.Met, fluorescence spec-troscopy, 522

Tyr-Tyr.Gly-Gly-Phe_Met, nuclear mag-netic resonance, 520

u

V-50,488, see trans-3,4-dichloro.N.methyl.N.{2.( l.pyrroJidinyl)-cyclohex yl]ben-ze neacetamide

U-69.593, see 5a,7a,8f3-( -)-[N-(7-(I-pyrro_

lidinyl)-I.oxaspiro(4.5)dec_8_yl)ben_zeneacetamideJ

Ultraviolet spectroscopy

559

f3.endorphin, 529-530enkephalins, 516, 522

v

Viminol. 444

x

X-ray crystallography, 166&-acetyl-I-iodocodeine. J67acetylmethadol, 453

a.allylprodine. 378

f3.allylprodine. 378arylpiperidines, 378-380azidomorphine, 167, 169

{4'Br.Phe4J-(LeuJenkephalin, 515[4'Br-Phe4J-(Met]enkephalin, 515codeine, /67-168

dextromethorphan. 167, 169

dextromoramide, 453

f3-dimethyl-4-phenyl.4-propionyloxypi.peridine, 378

Gly-Gly-Phe-Leu, 515

14-hydroxyazidomorphine, 1673-hydroxylevallorphan. 167, 169

isomethadone. 451

[LeuJenkephalin, 514-515meperidine, 378

[MetJenkephalin, 515

methadol. 453

methadone, 451

5-methylmethadone, 451

N-methyJnalorphine, 167morphine, 167-168, 173

nalbuphine, 167, 169

nalorphine, 167-]68

naloxone, 167-168

normethadone, 451

N.norpropoxyphene, 454oxymorphone, 167-1684-phenyJpiperidines. 378-380a-prodine, 378p.prodine, 378

propoxyphene, 453-45419-propylthevinol, 167, 169I ,2,&-trimethyl-4-phenyl_4_acetox ypiperi-

dine, 378

a-I ,2,3-trimethyl-4-phenyl-4-piperidinol,

378

56()

{3-I,2,3-trimethyl-4-phenyl-4-piperidinol,

378

'1-1 ,2,3-trimethyl-4-phenyl-4-piperidinol.

378a-l.2,S-trimethyl-4-phenyl-4-piperidinol,

378'1-1.2,5-trimethyl-4-phenyl-4-piperidinol.

378

Index

y-l.3,S-trimethyl-4-phenyl-4-propionoxy-piperidine. 378


z

Zactane, see Ethoheptazine

37747019 opiates 1986 george r lenz suzanne m evans d eric walters anton j hopfinger academic press...

Documents

morphinans references

chain analgesics references

molecular modeling of

enkephalins references

benzomorphans references

chemical anatomy of

structureactivity codeine

molecular modeling448