Arch. exper. Path. u. PharmakoI., Bd. 214, S. 214---226 (1952).

Department of Pharmacology University of Utah College of Medicine Salt Lake City, Utah

Equidistance Concept and Structure-Activity Relationship of Curarizing Drugs.*

By S. LOEWE and S. C. HARVEY.

With 2 figures.

(Eingegangen am 5. September 1951.)

I.

The chemical constitution of biological agents has many facets tha t may offer clues for the problems of structure-activity relationship (SAR 26, ~7), including the most fascinating one, that of selective activity. The spatial arrangement of the drug molecule represents only one par t of the large multiplicity of these facets. Yet it comprises in itself a large tridimensional variety of structural properties. The possible SAR significance of such architectural properties, pointed out more than five decades ago by EMm FISCHER and PAUL EHRLICH, has been elabora- ted more recently by HAUROWITZ 12, 2o and PAULING 31.

Recent students of SAR 1, 2, 3, 21-23, 3a, 35-3s, 42, 43, 45, by confining the

considerations of chemical properties to two or three presumably major "reactive groups" of certain agents and the considerations of spatial configuration to the linear distance between these groups, have placed emphasis on a streamlined, one-dimensional spatial-arrangement con- cept. The essential postulates of such an equidistance concept of SAR can be expressed as

RADd~u~ 1 = RADdr~g ~ = RADdru~ 3 . . . . . . . . . . . . . . . . . RADre¢¢ptor where RA are atoms of a specified type of bonding reactivity, D is the linear distance between them, and drugs 1, 2, 3, etc., are agents equally and maximally potent in the biological action concerned. "Receptor" is the biological partner of the hypothetical chemical reaction assumed to be the correlate and/or initiator of the alteration of biological function, which is the expression of drug action. The receptor partner of reactions falling under the equidistance hypothesis carries R/ks capable of reacting with those of the drug by virtue of bonding reactivity and mutual distance. The formula thus expresses tha t the distance at which the

* Extension of a paper given at Fall Meeting of the American Society for Pharmacology and Experimental Therapy, Boston, Mass., November 13--15, 1950, and published in abstract form 2s.

E quidistance Concept and Structure-Activity Relationship of Curarizing Drugs. 215

RAs are a r ranged in the recep tor is the d e t e r m i n a n t of chemical selec- t i v i ty , and the local and the physiological role of the recep tor are the de t e rminan t s of funct ional se lec t iv i ty of the drug act ion*.

I I .

Among var ious appl ica t ions of th is concept , t h a t to curar iz ing drugs is a t t r a c t i v e because of m a n y in te res t ing ramif icat ions . F r o m 1907 on, when WILLST.~TTER and HEUBN~R 44 descr ibed the first curar iz ing bis- t r i m e t h y l a m m o n i u m po lyme thy l ene ( later a b b r e v i a t e d as C 4), more and more evidence accumula ted which d e m o n s t r a t e d t h a t such "double- heade r s " can be more selective curares t h a n comparab le mono-ammoni - ums 1, 2, al, 82, 38 which m a y be categorized as curare t ype I . Such facts can invi te an equid is tance hypothes is , and indeed BARLOW and ING had an equid is tance concept in mind when t hey proposed to find those homologs of WILLSTATTER'S and HEUB~ER'S bis -onium te t ra - me thy lene in which the two cat ionic heads were wha t t hey called "an o p t i m a l d is tance a p a r t ' '2. I t is now obvious t h a t the inves t iga t ions of ]1~(~'S 1, 2, 1)ATO~I'S30-33 a n d PFEIFFER'S 22, 23, 35 groups and of more recent

workers are a classical example of serendipi ty . They did not y ie ld d a t a on the linear distance of the reac t ive a toms; ins tead, t h e y po in ted to the fasc ina t ing poss ib i l i ty t h a t curare ac t i v i t y is cor re la ted to the chain length of the in te r jacence be tween the two reac t ive on ium-ni t rogen a toms and t h a t highest po t ency is p re fe ren t ia l ly embodied in bis- oniums in which nine to twelve ser ia l ly a r ranged a tomic l inks can be coun ted as components of the in te r j acen t chain. As shown in column 5 of Table l , chains of such length indeed appea r as the in ter jacences of one or more of the represen ta t ives of the four ma jo r t ypes of eurar iz ing bis-oniums. They cons t i tu te the single-row in ter jacences of some of t he

* This formulation of the essence of SAI~ concepts based upon equidistance considerations is bclievcd to be a correct presentation of those equidistance (ED) hypotheses whose authors have clarified their ideas by appropriate definitions, as well as a fair attempt of presentation of those ED hypotheses which lack such definitional clarification. - - In one regard we have deviated from previous ter- minology. The expression "reactive atoms" is here employed where previous authors speak of "reactive groups". Even when one disregards that the reactivity of an atom always depends on factors contributed by the rest of the molecule, it is true that there are exceptional cases in which even an outstanding and critical bonding capacity is difficult to correlate with a single atomic component of the molecule, as for instance cases of resonance. On the other hand, such reactivity is rarely embodied in the entirety of a multi-atomic radical (= group); usually it is easy to point out the reactive atom within the reactive group. At any rate, reference to "reactive groups", when intramolecular distances are a major issue, introduces elements of ambiguity and arbitrariness. Indeed, whereas definite "distances of reactive groups" appear often in the literature, it is not often that the reader is told what parts of the "reactive groups" were selected as the starting and endpoints of the stretches measured.

216 S. LOEWE and S. C. It~vEY:

simple bis-trimethylammonium polymethylenes ("Cn"; type II) and of related synthetics in which the cationic nitrogens are incorporated in more complicated heterocyclic heads (type V), and they can be found in one or both of the two interjacent rows in certain natural curares (types I I I and IV). Two types of this class of compounds with "two- row" interjacences can be distinguished according to whether the two chains which constitute the circular double-interjacence contain the same (type III) or an unequal number of links (type IV).

III .

I f the similarity in the number of interjacent atomic chain links were found to be paralleled by a similarity in what PATO• a0 called the "spatial location" of the reactive N-atoms, these drugs might indeed

Figu re 1. Molecular modcl of (d-- ?) tubocurar ine . The whi te a toms , m a r k e d w i t h a " ÷ " , are the two on ium ni t rogens , t he i r l inear d i s tance (RAD) be ing m a r k e d by the b r acke t below the

p ic ture . The b r acke t a t the upper r i gh t m a r k s the m a x i m u m d i a m e t e r of the molecule.

offer support to the equidistance hypothesis. At least for the bis-oniums of types I I I and IV it is obvious in advance that chain length and RAD are rather unrelated. The roughly circular arrangement of their "two- row" interjacence imparts to these molecules the shape of a diadem

Equidistance Concept and Structure-Activity Relationship of Curarizing Drugs. 217

with two nitrogen "gems", as is illustrated in Figure l, the molecular model of d-tubocurarine*. In such diadem structures RAD, being the length of a chord of the circle, is necessarily shorter than the length of the corresponding arc ( ~ chain length). At any rate, for every endeavor to put the problematic parallelity to test it is prerequisite to determine the actual I~AD. For this purpose, the linear RADs were measured in FISHER-HIRSCHFELDER models of representative curare agents. The values obtained are presented in Table l, columns 7 and 8, together with other pertinent data.

I t would be difficult to find a common denominator for curarizing potency in any set of values presented in Table 1. Even the ratios between RAD and curarizing potency (columns l0 and l l ) lack uni- formity. Above all, the N-to-N distance (columns 7 and 8) has no fixed value in any of these curares; it varies in every single model according to the vagaries of measurement, and the range of variation (column 9) is especially great in highly potent substances. This is due to the lack of rigidity of the interjacence (column 6), which is easily explained by the uninhibited rotations around a varying number of the bonds between the serially arrayed links of the interjacent row. A cardinal lesson taught by these measurements is that the length of a chain is not necessarily the measure of the straight distance between its endpoints and tha t a flexible connection between two points is not an appropriate device to keep them at a fixed distance apart. Accordingly it appears that , for substantiation of the equidistance (ED) hypothesis, compounds with an immovable, solid-frame interjacence are needed; such substances are not among the known curarizing bis-oniums.

The molecular models do not depict the strong cationic charges of the reactive atoms. However, this factor is implicitly considered in our measurements. I f such charges cause a mutual repulsion of the reactive heads, which keeps them maximally apart, then their spatial location is expressed by the maximum RAD values measured (column 8). These maximum distances, too, differ from substance to substance, and for approximately equipotent curares in a range as wide as ~ 49~o (com- pare, for instance, substances No. 9 and 17 with No. 13 and 16). There- fore, until circumstances can be demonstrated by which an interjacent chain can be stretched in marked excess of its maximum extensibility, the representative with the greatest maximum RAD (No. 17 of Table 1) cannot possibly determine the distance constant postulated by the ED

* The portrait of the tubocurarine molecular model is also illustrative of the difference between the bulky build of these molecules with "two-row" interjacences and the slender thread molecules of the simple one-row interjacence polymethylene curares, a difference very aptly emphasized by BOVET in his recent suggestion of the terms "pachycurares" for the former and "]eptocurares" for the latter.

Arch. exper. Pa th . u. Pha rmako l . , Bd. 214. 1 5

218 S. LOEWE and S. C. HARVEY:

Table 1. Curarizing Potency and Reactive Atom Distance*.

Curr. 1~o.

2 3 4

5 6 7 8

9

10 11

12

13

14

15

16

17

Substance

tetramethyl- ammonium 33

C 4 s3

C 5 33 C 6 as

C 9 as C 10 33

C Ii 33 C 12 33

C 18 33

d-tubocurarine isomeric tubo- curarines 24 dimethyl-d- tubocurarine 39

N-methyloxy- acanthine 23

pentamethyl- enc-bis-(N- ethyl-8-quino- linium) ether 4 decamethylene- bis-atropinium 2~ pentamethylene- bis-atropinium32 pentamethylene- bis-(N-methyl- atropinium) ether s3

3 4 5 6

Curar Number I I . . 1 of I Rigid- Type p~mgcy atoms i ity

P of N-to-N row

I [I [I [I

[I [I [I [I

[I

[I

[I

V

V

V

V

V

0.06 0.0014 0.0027 0.0052

1.01 1.47 0.94 0.42

1.12

1.00

0.025

7.8

0.76

0.75

2.5

0.43

0.42

0 4 5 6

9 10 l l 12

18

10(10)

10(10)

10001

9(]2)

11

10

5

21

n, le m d.

mi: ira.

mi: ira.

8 1 9 1011, Linear RAD (~) RatioRAD/PR

man max e/min

(4.5) 6.0 4.8 5.0

4.8 4.8 4.5 4.6

(~) 7.0 8.5 9.9

14.0 15.3 16.7 18.0

26.5

12.5

14.0

12.5

12.5

11.0

15.2

8.5

27.5

(lOO) 8

28 33

49 52 58 59

71

35

50

42

41

56

45

26

68

(75) (~) 4285 5O0O 1175 3150 963 ~1923

4.8 14 3.3 10 4.8 18 11 43

4.0 24

6.0 12.5

189 560

D.65 1.6

6.8 17

4.4 15

2.3 6

11.6 20

11.5 60

* "Curarizing Potencies" (P; column 4) are calculated from Median Rabbit Headdrop Doses (HDs0) in reference to HDso of d-tubocurarine (P ~ HDs0 of d-tubocurarine/HD30 of substance in question); all HDs0 values originate from publications quoted in column 2. In the designations of the onium salts, enumerated in column 2, their anion moieties are omitted for the sake of brevity; it should, however, be mentioned that potency varies considerably with the anion associated (for details consult the references given). - - "Number of Atoms" (column 5) is that of the shortest N-to-N row; for substances with double-row interjacence the number of atoms in the second row is added in parenthesis. - - Column 9 gives the range between minimum and maximum RAD measured, expressed as per-cent deviation (=k) to either side from middle value [ ± % range ~ 100 (Max. R A D - - Min. RAD)/(Max. RAD--Min . RAD)]. - - RAD measurements given for substances No. 10 and 11 are interchangeable, because the spatial arrangement at the asym-

Equidistance Concept and Structure-Activity Relationship of Curarizing Drugs. 219

hypothesis. I f the ED hypothesis were centered on any RAD smaller than that of the drug having the greatest RAD, the same prerequisite of hyper-extensibility would have to be fulfilled by every equipotent representative having an interjacence which even in the state of maxi- mum extension is shorter than that assumed to represent the distance of fit. In addition, however, the interjacences of all representatives having greater chain length would have to be bent into the distance of fit. The greater the force of repulsion between the l~As, the greater an energy would be needed to force the reactive heads of the curares with excessively long chains into a receptor distance of appropriate fit for equipotent compounds with shorter chains. I t should also be con- sidered that, if mutual repulsion determines RAD, necessarily each RAD in a point-symmetrical "three-header" is much smaller than the more optimal RAD in the corresponding one-axially symmetrical "double-header", whereas the potency of the latter in instances is con- siderably smaller (cf. Flaxedil, page 221).

Thus, the exceptions to two major postulates implied in the above formula of the ED hypothesis, namely, that compounds with equal I~AD should be equipotent and compounds of unequal RAD should not, are more frequent than the cases conforming to those postulates. Like- wise frequent are the exceptions from a further implication of these two postulates, namely, from the postulate that in each homologous series of bis-onium compounds the potencies of the representatives should gradually or abruptly approach from both sides a potency maximum embodied in the representative having the optimum inter- jacent chain length. Three examples of such exceptions are the series of bis-triethyl-ammonium methylenes (BTEAn), in which the potency ratio BTEA 13/BTEA 4, i. e., that between the 13-C and the 4-C homo- log, is much smaller than in the analogous trimethyl series, and the analogous bis-quinoliniums and bis-stryehniniums, in which the potency ratios BQ 10/BQ 5 and BS 5/BS 2 are approximately 1.01.

IV.

All the preceding considerations emphasize that the structure of the interjacence may be more important than its length. Naturally, the interjacence of all bis-quaternary curares extends in three dimensions (compare footnote, page 217), and that makes it comparable with other appendages of reactive radicals, discussed in SAR contexts as "umbrella"

metric C atoms of the known isomeric tubocurarines is as yet unknown; arbitrarily the structure depicted in Figure 1 in one of its possible positions was assumed as that of d-tubocurarine, and the two extreme values from all other arrangements constructed are given sub No. ll .

15"

220 S. Lo~wE and S. C. I - I~vnv:

s t ruc tures . Their funct ion is st i l l obscure, bu t t h e y are known to be ind ispensable a t t r i bu t e s of cer ta in biological agents.

Prominent examples are presumptive blocking agents such as antihistaminies and anticholinergics. In such drugs, the actions of which are often ascribed to spatial competition for a receptor site, the umbrella structure may function by some passive interference due to size and shape of the appendage, for example, an "adumbrating" influence which may hamper the access of substrate or other material to a biologically important site.

Figure 2. Adumbra t i on of circular area (black) on receptor surface by var ious homologous bistr i - me thy l ammon ium polymcthylenes. -- The whi te areas arc the shadows of the i nd iv idua l homologs, the large numeral des igna t ing the number of mcthylenes (4 to 13) in the N-to-N interjacence. Three different adumbra t ion effects of C 13 are depicted (bot tom row) according to three different posi t ions of the in te r jacent pa r t of the molecule. -- Tile smal l numeral along central upr igh t line designates project ion (in A) of " u m b r e l l a " interjacence from middle of N-to-N connection line. --

For fur ther explana t ion compare text .

Appl ied to the homologous Cn series, the poten t ia l i t i es of adum- b r a t i on m a y be i l lus t ra ted by the const ruct ions of F igure 2. The p ic tures represen t shadow projec t ions of the molecular models of C 4 to C 13, all the molecules being kep t under a r b i t r a r y bu t comparable axia l and R A D condit ions. The shadows fall upon a p lane in which a s t ra teg ic a rea is m a r k e d b y a b lack circle whose center is a t 5 _~ ver t ica l d is tance f rom the middle of the N- to -N line. As shown in F igure 2, the shadows of the lower homologs are too shor t to a d u m b r a t e the ent ire s t ra tegic

Equidistance Concept and Structure-Activity Relationship ofCurarizing Drugs. 221 '

area, t h o s e of C 13 and higher homologs too mobile to s t ay in t he same posi t ion all the t ime. Thus, in this example , comple te a d u m b r a t i o n is indeed l imi ted to the p e a k - p o t e n t homologs C 9 to C 12.

This example is en t i re ly a rb i t r a ry . I t is no t offered as a new e x p l a n a - t ion of SAR of the curares, bu t only employed to d raw a t t e n t i o n to o ther possibi l i t ies of re la t ing s t ruc ture and ac t iv i ty . The poss ib i l i t ies of umbre l la funct ions go beyond mere pass ive adumbra t ion . All in te r - jacences, even simple non-subs t i tu t ed po lymethylenes , ca r ry g roups react ive b y shor t - range, some also by long-range, forces b y which t h e y m a y pa r t i c ipa t e in the pharmacologic react ion, a t least by o r i en ta t ing the adumbra t ion . Accordingly , in ter jaccnces can come into p l a y b y v i r tue of the i r own spa t i a l and energet ic " f i t " r a the r t h a n as spacers be tween RAs.

There is indeed ample evidence t h a t curare ac t i v i t y of congeneric b is -oniums which differ only ins ignif icant ly in N- to -N dis tance var ies With the spa t ia l and energet ic proper t ies of the i r in ter jaeence.

Examples are: the high potency ratios (PR) between d-tubocurarine and its laevorotatory isomer (Pl%: 30 to 6024), between the methyl ether of d-tubocurarine and the free-alcohol parent substance (PLY: 83°), between bis-onium single-row esters of equal chain length which differ only by a permutation of their oxo groups, for instance, between the homobetaine di-ester of propylene glycol and the betaine di-ester of butanediol-l-4, (PLY: 300 TM, 19) and between the di-choline ester of terephthalic acid and the homobetaine di-estcr of hydroquinone (PR: 91°, 19). The example of Bovm's and his associates' triethyl-aminoethoxy substituted benzenes 1° is particularly instructive. The 1,2,3-tris-substituted benzene, Flaxedfi, is three times as potent as the 1,2-bis-substituted compound (which, in turn, is 13 times as potent as the 1-trimethylaminocthoxy-benzene). In both substances nature and sequence of the chain links between the nitrogens are the same and the number of links varies only between 8 and 9, but the linear N-to-N distance, if determined by the mutual repulsion of the charged heads, is certainly different. I t is greater (12/~), hence closer to the hypothetical optimal RAD, in the less potent bis-onium, in which the nitrogens are supposedly at the opposit9 ends of the maximally extended chain, than in the tris-onium, in which the nitrogens presumably form the corners of a near-to-equilateral triangle of m~ximally 10/~ side length. On the other hand, the more potent tris-onium would seem to grant a greater probability of combination of any two of its RAs with the receptor RAs (cf. comparable considerations of Ing in application to bis-oninm versus mono- onium compounds) ; the more potent tris-onium also possesses a larger interjacence capable of adumbrating a greater area.

Na tu ra l ly , all these considerat ions hold o n l y when poss ible bio- chemical differences be tween the drugs, as in absorp t ion , exc re t ion and metabol ic fate, are disregarded.

V°

Two major presupposi t ions of the E D hypothes i s are the s t ruc tu ra l one that~ a l l curar iz ing agents have a measurab le in te r -on ium dis tance , and the biological one t h a t t h e y all have the same mechanism of ac t ion.

• 222 S. LOEWE and S. C. HARVEY:

The s t ruc tu ra l p resuppos i t ion is i nva l i da t ed b y the numerous po t en t cura r imimet ics which are no t bis-oniums.

They are either hemi-quaternized diamines, such as 2-(2-diethylamino)amyl- aminobenzoquinone methobromide (I; P----2.018), 2-piperidylpropylaminobenzo- quinone methobromide (II; P =2.01s), N-propylquinolinium bromide (III ; P ~ 0.0615), 5-dimethylaminopentanoylcholine (IV; P ~ 0.041s), C-toxiferine-I (V; P = 3941) and C-curarine-I (VI; P = 0.7541); or simple mono-oninms, such as tetramethy]ammonium (P = 0.06 to 2.01, 33}; or non-quaternary diamines, such as stflbamidine (P = 0.083) and nicotine (VIIle); or non-quaternary mono- amines, such as dihydro-beta-erythroidine (VIII; P = 0.1 is). I t cannot be assumed that additional quaternization in the body brings these substances into line with the ED hypothesis; whereas quaternization increases curare activity in some of them, e. g., in the weakly potent diamine IV, it does not markedly change activity in others, and actually diminishes the potency of some, e.g., of certain quinol- iniums 14, of VIII 4° and of nicotine. Thus, to all these curares the formula of the ED hypothesis is not applicable, because they have only one RA.

The biological p resuppos i t ion is i nva l i da t ed b y the ever-growing amoun t of evidence t h a t the so-called curar iz ing drugs are d iv ided into two* separa te pharmacologic classes, the class of "cu ra re - l ike" drugs in the s t r ic t sense and the class of depolar iz ing drugs (PATOIS°).

The former interfere with neuromuscular transmission by desensitizing the end-plate to the depolarizing action of aectyleholine; the latter, however, act by depolarizing the synaptie membrane and lowering the excitability of the adjoining muscle membrane**. These entirely different modes of action can hardly be brought upon a common denominator of identical mechanism and receptor.

However , the v e r y collapse o f these premisses could give rise to modif ied and more c lear ly out l ined E D concepts i f the demarca t ion line be tween the two s t r u c t u r a l classes, the bis-oniums and the non- bis-oniums, and t h a t be tween the two pharmacologic classes, the desensi t izers and the depolarizers , could be shown to coincide. The necessary pharmacologic classif icat ion of all known blocking agents of neuromuscu la r t ransmiss ion is far f rom being completed.

For most of them the class criteria established mainly by PATON and his associates--such as: degree of antagonism by physostigmine and C 5 and of syn- ergism by ether, ratios of species sensitivities, red muscle/white muscle sensitivity ratio, histamine liberation, isosensitization have as yet to be determined.

I ron ica l ly enough, however , the two agents most t ho rough ly classi- fied, d - tubocurar ine and" C 10, the ma jo r witnesses for the E D hypo- thesis because of the concomi tance of equal and high po tency and of equal number of i n t e r j acen t chain l inks and op t ima l R A D , are now ascer ta ined to be the p ro to types of the two cont ras t ing pharmacologic classes, the former embody ing the t r u l y curarel ike, the l a t t e r the depo- lar izing ac t iv i ty .

* Really, four or more classes 3° can be distinguished, but the present discussion can be limited to the two specified here.

** Compare, for instance, the particularly lucid review of FELDB~Ra in this Archiv, 212, 64, 1950.

Equidistance Concept and Structure-Activity Relationship of Curarizing Drugs, 223

VI.

That the "transformation ''25 of pharmacologic potentialities of a drug into pharmacologic effect proceeds by way of a chemical reaction between the drug and some component of the organism--more recently called "receptor"-- , is probably the oldest axiom of pharmacology. To identify the receptor for a drug complying with the axiom, and to express the transformation in terms of the particular chemical reaction and the biological sequels in terms of the alteration of the receptor, is the coveted goal of the student of SAR. I t is on the approaches to this goal, tha t he endeavors to predict the receptor from the structural properties of drugs having a certain biological effect in common.

The equidistance concept of curarizing drugs hypothesizes that the transformation, by which they interfere with neuro-muscular trans- mission, consists in the bonding between a pair of quaternary o n i u m groups in the drug molecule and a pair of co-reactive groups in the receptor molecule, the selectivity of the reaction being determined by congruity of the two intramolecular distances between those pairs of reacting groups. As is shown above, this two-point-landing hypothesis is unsatisfactory because it fails to explain why so many active and selective drugs lack either the stipulated landing gear or its postulated dimensional arrangement and why landing of two equally qualified drugs at supposedly equally qualified mooring places can be ensued by notably different biological sequels. Obviously, the main structural characteristics claimed by the hypothesis are not indispensable com- ponents of the equation for curarizing activity; other factors enter the equation and are at least as important determinants as number and distance of the postulated RAs.

Thus, whereas the hypothesis has turned out to be remarkably fruitful in finding new synthetic curares, its heuristic value in contri- buting to an understanding of the mechanism of transformation is as questionable and as irreconcilable with present knowledge as, for in- stance, the SAR hypothesis of a dominant role of the presence and number of ethyl groups in hypnotic agents, which may have appeared acceptable in the pre-barbiturate era 1~. The fictitious example of an application of adumbration concepts, given in a preceding section to add a constructive element to the analysis of the equidistance hypo- thesis, was chosen to emphasize the need for a return from one-dimen- sional simplifications to a more complex, stereoscopical thinking in line with the old concept of the key-and-lock eomplementariness between selective agents and their biological substrate. The undeniable SAR significance of what in curarizing drugs with two radicals of particularly pronounced chemical reactivity represents the interjacence, in those

224 S. LOEWE and S. C. HARVEY:

with only one outstanding bonding capacity an umbrella appendix, should certainly facilitate the turn from premature streamlining to a fuller appreciation of the tridimensional potentialities of the "Gesta l t" of the curarizing drugs.

Summary.

1. In a selection of representatives of the four major types of bis- quaternary ammonium compounds selectively interfering with neuro- muscular transmission and of some congeners lacking such selectivity, the linear intramolecular distance between the two reactive onium nitrogens was measured in molecular models.

2. The reactive a tom distance was found to be variable over a wide range in each individual compound, multiple rotation about atomic bonds along the N-to-N interjacence allowing variation of the spatial arrangement of the molecule.

3. From no aspect, including the assumption tha t the maximum N-to-N distance is prevalent because of the mutual repulsion of the cationic heads, was it possible to find any correlation between selective activity and the reactive a tom distance.

4. These observations and a discussion of other pertinent data were employed to evaluate the hypothesis that the N-to-N interjacence of bis-onium compounds serves as a rigid spacer of the cationic heads and that curarizing activity is explained by the reaction of optimally spaced onium groups of the drug with equidistant co-reactive groups of a biol- ogical receptor substance (equidistance hypothesis of curarizing activ- ity). I t is concluded tha t the equidistance hypothesis in its present form cannot be reconciled with the facts known about any of the various types of drug interference with neuromuscular transmission and the prominent representatives of these activities.

5. In order to demonstrate tha t with no lesser ease diametrically opposite concepts can be formed, in which the emphasis is shifted from the mere spacer role of the interjacence to the details of the spatial arrangement of the interjacence, an example is presented of the appli- cation of an "adumbrat ion" hypothesis of curarizing activi ty to the series of bis-onium polymethylenes; in contrast to the equidistance hypothesis, this hypothesis applies to non-bis-onium compounds as well as to bis-oniums.

6. The adumbrat ion hypothesis, though by no means offered as an explanation of curarizing activity, is found useful to accentuate the necessity of a return to considerations of the total i ty of tectonic and bonding potentialities which determine the spatial and energetic fit between drug and receptor.

Equidistance Concept and Structure-Activity Relationship of Curarizing Drugs. 225

Zusammenfassung. 1. Ffir ausgew~hlte Vertreter der vier Hauptgruppen bis-quaterni~rer

Ammoniumverbindungen, die selektiv die neuromuskul~re Reizfiber- tra'gung beeintr~el4tigen, und ffir einige verwandte Substanzen, denen diese Wirkung fehlt, wurde der geradlinige Abstand zwischen den beiden reaktiven Onium-Stickstoffatomen an Molekiilmodellen gemessen.

2. Der Abstand der reaktiven Atome wurde in jeder Verbindung in einem weiten Bereich schwankend gefunden, da vielfi~ltige Rotation um die Atombrficken entlang dem Zwisehenstfiek zwisehen den beiden Stickstoffatomen st~ndige Ver~nderungen der r~umlichen Anordnung des Molekfils erlaubt.

3. Unter keinem Gesichtspunkt, auch nicht unter der Annahme, dab wegen der wechselseitigen Abstol~ung der kationischen Endradikale der maximale N-N-Abstand der vorherrschende ist, konnte eine feste Be- ziehung zwisehen selektiver Wirksamkeit und dem Abstand der reaktiven Atome gefunden werden.

4. Diese Beobachtungen und eine ErSrterung anderer einsehl~giger Erfahrungen wurden zu einer Beurteilung der Hypothese verwendet, dab das N-N-Zwischenstfick der Bis-onium-Verbindungen als starre Verspannung zwischen den kationisehen Endgruppen dient und daB Curarewirksamkeit sich aus der Reaktion optimal verspannter Onium- gruppen des Pharmakons mit im selben Abstand angebrachten co- reaktiven Gruppen einer biologischen Reeeptorsubstanz erkli~rt (gqui- distanzhypothese der Curarewirksamkeit). Es wird der Sehlul] gezogen, daB die ~quidistanzhypothese in ihrer gegenwi~rtigen Form mit den heutigen Kenntnissen fiber die verschiedenen Arten d.er Beeintr~chti- gung der neuromuskuli~ren Reizfibertragung und fiber die Spitzenver- treter ffir diese Wirkungsarten nicht in Einklang ist.

5. Um zu zeigen, dab man sich nieht weniger schlfissige Vorstellungen ganz entgegengesetzter Art bilden kann, in denen der Sehwerpunkt yon der bloBen Verspannerrolle des Zwischenstficks auf die Einzelheiten von dessen Raumerffillung verlegt ist, wird ein Beispiel der Anwendung einer ,,Beschattungs"-Hypothese der Curarewirksamkeit auf die l~eihe der Bis-onium-polymethylene erSrtert.

6. Die Besehattungshypothese, die im Gegensatz zur J(quidistanz- hypothese auch auf Nicht-Bis-onium-Verbindungen angewandt werden kann, wird zwar keineswegs als eine Erkliirung der Curarewirksamkeit, aber doch als nfitzlich betrachtet, um die Notwendigkeit einer Rfickkehr zur Berfieksichtigung der Gesamtheit der molekularen Bau- und der da- dureh gegebenen Bindungsm5gliehkeiten zu betonen, die den riiumlichen Sitz und energetisehen Effekt des Pharmakons am ,,Receptor" be- stimmen.

226 S. LOEWE and S. C. HArvEY: Equid is tanee Concept and St ructure-Act iv i ty .

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