design, synthesis and some uses of receptor-specific agonists and antagonists of vasopressin and...

JOURNAL OF RECEPTOR RESEARCH, 13(1-4), 195-214 (1993)

MINIREVIEW

DESIGN, SYNTHESIS AND SOME USES OF RECEPTOR-SPECIFIC AGONISTS AND ANTAGONISTS OF VASOPRESSIN AND OXYTOCIN

Maurice Manning* and Wilbur H. Sawyer' *Department o f Biochemistry and Molecular Biology, Medical College o f Ohio, P.O. Box 10008, Toledo, OH 43699-0008 and 'Department o f Pharmacology, College o f Physicians and Surgeons o f Columbia

Un ivers i ty , 630 West 168th St ree t , New York, NY 10032, USA

ABSTRACT

Se lec t i ve agonists and antagonists are powerful t o o l s f o r s tud ies on AVP and OT receptors and on the phys io log ica l and pathophysiological r o l e s o f AVP and OT. Here we show how some o f these pept ides and t h e i r rad io labe l l ed de r i va t i ves were designed. We a l so present examples o f the c u r r e n t l y ava i l ab le c y c l i c and l i n e a r OT and AVP agonists and antagonists from our l abo ra to r ies .

INTRODUCTION

To date the f o l l o w i n g receptor subtypes f o r a rg in ine vasopressin (AVP) and oxy toc in (OT) have been charac ter ized (1-4): AVP Vla, AVP Vlb, AVP V,, and OT u t e r i n e receptors. V,, receptors modulate the vasopressor ac t ions o f AVP. They have been shown t o be present i n many t i ssues i nc lud ing b r a i n (3). AVP V,, receptors modulate t h e ACTH re leas ing e f f e c t s o f AVP from the a n t e r i o r p i t u i t a r y (2). Both the V,, and V,, receptor subtypes a c t v i a the phosphoinosi t ide pathway. AVP V, receptors, present i n the rena l t ubu le and c o l l e c t i n g duct, modulate a n t i d i u r e t i c responses t o AVP. V, receptors mediate t h e i r ac t ions v i a c y c l i c AMP. Oxytocin receptors are present on the u te rus and on the mammary gland and mediate the u t e r i n e con t rac t i ng and m i l k - l e t down e f f e c t s o f OT (4) .

195

Copyright 0 1993 by Marcel Dekker, Inc.

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196 MANNING AND SAWYER

Since the o r i g i n a l synthesis o f oxy toc in and vasopressin by du Vigneaud and col leagues i n the mid f i f t i e s (5-6), many labo ra to r ies have j o i n e d i n the search f o r agonists and antagonists s e l e c t i v e f o r the d i f f e r e n t receptor subtypes f o r these two neuropeptides. (For reviews see r e f s . 4, 7-10).

I n recent years many o f the s e l e c t i v e agonists and antagonists, i nc lud ing i n some cases the t r i t i a t e d and rad io iod ina ted de r i va t i ves which have resu l ted from these studies, have found widespread use as

pharmacological probes o f t he known and p u t a t i v e phys io log ica l and pathophysiological ac t ions o f OT and AVP ( f o r reviews, see r e f s . 10-

12). The therapeut ic p o t e n t i a l o f some AVP and OT agonists has been c l e a r l y d e m o n s t r a t e d (12). V, a n t a g o n i s t s have p o t e n t i a l therapeut ic value f o r t h e t reatment o f SiADH (9,lO). OT antagonists could be o f value i n the prevent ion o f premature l abo r (10-12, 34).

Our l abo ra to r ies have been very a c t i v e i n the area o f AVP and OT agonist and antagonist design f o r t he past 25 years (10,13) and have r e c e n t l y uncovered a new c lass o f l i n e a r AVP antagonists and agonists (10,13,28,43,44). The M e r r i f i e l d s o l i d phase method (14) has been o f inest imable value i n these s tud ies (10,ll). Space considerat ions do n o t permi t p resenta t ion o f work i n t h i s area from other labora tor ies . A lso, t he reviews c i t e d above should be consulted f o r most o f the o r i g i n a l references t o the synthesis and pharmacological eva lua t ion o f t he numerous pept ides presented here. De ta i l s and references t o the bioassay methods are given i n r e f s . 10, 11. Here we w i l l focus on advances i n OT and AVP agonist , antagonist and rad io l i gand design c a r r i e d ou t i n our l abo ra to r ies . The rad io l igands were developed i n c o l l a b o r a t i o n w i t h S . Jard, C. Barberis and t h e i r col leagues i n Montpe l l ie r , France. We w i l l a l so b r i e f l y discuss some o f the many labo ra to ry uses o f these pept ides and t h e i r p o t e n t i a l as therapeut ic agents.

Potent and/or s e l e c t i v e AVP and OT aqonists (Table 1)

Oxytocin and vasopressin have the f o l l o w i n g s t ruc tu res :

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AGONISTS AND ANTAGONISTS OF AVP AND OT 197

NH.. 1 2 3 4 5 6 7 8 9 % ,CH-CO-Tyr-Ile-Gln-Asn-Cy-Pro-Leu-Gly-NH,

CH, I

OT

NH2, 1 2 3 4 5 6 7 8 9 CH-CO-Tyr-Phe-Gln-Asn-Cy-Pro-Arg-Gly-NH,

S S

AVP

I 0 CH,.

They d i f f e r on l y a t pos i t i ons 3 and 8. Because o f t h e i r s t r u c t u r a l s i m i l a r i t y , they possess the a b i l i t y t o i n t e r a c t w i t h each o ther 's receptors. Thus OT can b ind t o and a c t i v a t e V,, and V, receptors and

AVP can l i kew ise b ind t o and ac t i va te OT u te r i ne receptors. However, as can be seen from the pharmacological data i n Table 1, it has been poss ib le t o modify OT and AVP t o g i v e molecules which possess g r e a t l y enhanced s e l e c t i v i t y f o r a given receptor subtype r e l a t i v e t o e i t h e r OT o r AVP. Thus [Thr4,G1y7]0T i s a h i g h l y se lec t i ve agonist f o r OT u te r ine receptors (11). VDAVP (11) and dTyr(Me)VDAVP (37) are h i g h l y se lec t i ve agonists f o r AVP V, receptors. [Phe2,0rna]VT (11) i s a se lec t i ve agonist f o r V,, recep- to rs . 1-deamino[D-3- (pyridyl)Ala2]AVP i s a recen t l y discovered se lec t i ve agonist f o r V,, receptors (15). Many o f the se lec t i ve agonists i n Table 1 have been found t o be valuable pharmacological probes i n s tud ies on AVP and OT receptors. A number have a l so been t r i t i a t e d (see Table 7) and some are prov ing t o be very use fu l rad io1 igands f o r receptor l o c a l i z a t i o n and charac ter iza t ion . F ina l l y , as can be seen below, many o f s t r u c t u r a l mod i f i ca t ions which produced the se lec t i ve agon is t i c pept ides i n Table 1 proved t o be h i g h l y s i g n i f i c a n t i n the design o f AVP and OT antagonists.

Desian o f Cvc l i c and l i n e a r antasonists o f AVP and OT: Backsround

AVP and OT antagonists now f a l l i n t o 3 classes: (1) cyc l i c , (2) l i n e a r and (3) non-peptide. Tables 2-6 l i s t examples o f non-

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TABLE 1. Analogs more Potent and/or m r e Se lec t ive than Oxytocin and Vasopressin

Vla Receptor V Receptor Oxytocic (0) Vasopressor (P) A n t d i u r e t i c (A)

Peptide (Un i ts/nrg) (Un i ts/nig) (Un i ts/mg) O/A O/P

OT' dOTa [Thr4] -0T' [Th<.Gly:] -0T' [HO 3 [Thr ]OTa

AVP' Tyr ( Me)AVPb

[HO] AVP' dAVP' dTyr (Me)AVPC

d0AVP'

dVDAVP'

dTyr( Me)VOAVPc

VDAVP'

[Phe20rn8] -VTa d[D-3PAL]VPd

520 803 923 166

4,179

14 antagonist

(PA, =,7.44) ( i n v i t r o )

31 63

antagonist (pA2 =.7.41) ( i n v i t r o )

- 1.5 0.60

8

antagonist (pA2 =,7.38) ( i n v ivo)

1

4 1.4 0.4

< 0.01 4.92

373 9.7

549 346 4.1

0.39 0.037

antagonist

an agonist (PA, = 7.01)

124

4 19

0.9 0.002 5.3

320 386

467 1.745

830

,200 653

,230

,740

0.55

130 42

513 83,000

790

u 0.9 40

0.9 5

202

- 3,000 17,650

i n f i n i t e

i n f i n i t e

121 553

2,146 > 16.600

850

m

255 antagonist 1

(pA2 = 6.22)

'For o r i g i n a l reference see r e f . 11. Oxytocic a c t i v i t i e s were assayed on iso la ted r a t u t e r i suspended i n a Mg2+-free so lu t ion . bOata from r e f . 24. 'Data from r e f . 37. dOata from r e f . 15. This i s a se lec t ive Vlb agonist . d = 1-deamino; OT = oxytocin; HO = 1-Hydroxy (Hydroxyl group replaces a-amino group); AVP = arg in ine vasopressin; Tyr(Me) = 0-methyl tyrosine; OAVP

2 = D-Arg'VP; V = Val4; VT = vasotocin; 0-3PAL = D-3-(pyridy1)Ala .

selective and selective cyclic and linear OT, Vlay V,, and V, antagonists. The cyclic AVP and OT antagonists are all derived from analogs of the parent peptides. Non-peptide AVP V,, and V, receptor antagonists have also recently been reported (16y17). It should be noted that a new class of cyclic peptide OT antagonists derived from a bacterial source has also recently been reported (18).

The design of the cyclic AVP and OT antagonists in Tables 2-6 was greatly facilitated by the availability o f promising lead OT and AVP V,, antagonists from the du Vigneaud and Rudinger laboratories (4,7,8,10). Incorporation of the structural modifications in those

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leads into a number of the potent and selective agonists presented in Table 1, as described below, resulted in molecules which exhibited greatly enhanced OT and V,, antagonistic potencies and led indirectly to the discovery of AVP V, antagonists. The recent discovery of linear antagonists of AVP and OT (10,28,43,44) was totally unexpected; since for years it had been assumed that a ring structure was a sine qua non for binding to AVP and OT receptors (497).

Desiqn of oxvtocin antaqonists (Table 2)

Promising lead antagonists were discovered in the du Vigneaud and Rudinger laboratories (see reviews 4,7,8 and 10 for references). Two modifications in particular proved to be very valuable in OT antagonist design. 0-alkylation of the tyrosine at position two in OT and di-alkylation of the !-carbon at position one in OT and in the highly potent OT agonist dOT. One of the most potent i n vitro OT antagonists to emerge from those studies was [ l-(lI-mercapto-/t,B- cyclopentamethylenepropionic acid) oxytocin (d(CHJ50T) (19). It has the following structure:

1 2 3 4 5 6 7 8 9 ,CH,-CO-Tyr- Ile-G1 Leu-Gly-NH,

This was later shown to be an i n v i v o OT antagonist (38). Replacement of the Tyr2 by Tyr(Me)' and Leu' by Orn' led to a significant enhancement in anti-0T i n vivo potency (39). Further modifications at position 4 (Thr) and nine (deletion o f Gly-NH,) have led to significant improvements in anti-oxytocic potency and selectivity (40). Virtually all of the OT antagonists in Table 2 have been used in a wide variety of studies on the roles of OT and AVP. Two in particular are noteworthy: d(CH,),[Tyr(Me)',Thr4,Tyr- NH:]OVT when radioiodinated results in a labelled derivative which

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TABLE 2. Potent and/or Selective Cyclic and Linear Oxytocin Antagonists

Antioxytocic fin vivo) AntivasoDressor Antiantidiuretic

ED Pept ide EDa pAZb EDa pAZb EDa pA: Ratio'

d(CH,150Td 6.65 Weak d ( CH,) , [Tyr (Me) OVTe 4.2 7.37 0.80 7.96 agonist 0.2

(0.01 U/W)

d(CH ) [Tyr(Me)',Thr4]OVTf 2.0 7.55 9.9 6.85 - 330 - 5.3 5.0 d( CH:); [Tyr(Me)2.Thr4.Tyr-NH~]OVTf 1.0 7.83 6.6 7.02 agonist 6.6

desGlyNH,d( CH2), [Tyr (Me)', Thr4jOVTf 1.3 7.69 23 6.48 - 300 - 5.5 17 d(CH ) [D-Tyr(Et)%al4. Lys7VP 1.9 7.57 0.48 8.16 1.5 7.72 0.2 Aaa-a-?yr(Et)Phe-Val-Asn-Abu-Pro-Arg- 34 6.34 5.7 7.10 2.1 7.50 0.2

(0.015 U/W I

Gly-NH,'

'The effective dose (€0) is defined as the dose (in nananoles per kilogram) that reduces the response to 2x units of agonist to equal the response to lx unit. bEstimated in vivo pA2 values represent the negative logariths of the effective doses divided by the estimated volume of distribution (67 ml/kg). 'ED ratio = antivasopressor EO/antioxytocic €0. dData from ref. 38. eOata from ref. 39. 0-Tyr(Et) = 0-ethyl 0-tyrosine. Aaa = adamantaneacetyl. d(CH2)5 = [l-(8-mercapto-8,8-pentamethylenepropionyl] .

fOata from ref. 40. gOata f r a refs. 41 and 43.

i s h i g h l y se lec t i ve f o r OT u te r ine - t ype receptors (20). d(CH,),[D- Tyr(Et)2,Va14,Lys8]VP (40) has r e c e n t l y been converted t o a photo- a f f i n i t y d e r i v a t i v e which has been u t i l i z e d t o demonstrate t h a t AVP V,, and V, antagonist: receptor adducts, i n con t ras t w i t h AVP V,,

and AVP V, agonist: receptor adducts, are n o t i n t e r n a l i z e d (21).

Desiqn o f c v c l i c AVP V,, antaqonists (Table 32

The potent and se lec t i ve AVP V, agon is t dVDAVP (Table 1) was shown t o be a V,, antagonist (11). We had hoped t o convert i t t o a V, antagonist by use o f t he aforementioned cyclopentamethylene subs t i t u t i on , which du Vigneaud and col leagues had employed t o convert the potent oxy toc ic agonist dOT t o the OT antagonist d(CH,),OT (19). The r e s u l t a n t molecule d(CH,),VDAVP (42) which has the fo l l ow ing s t ruc tu re :

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TABLE 3. Potent and Selective Cyclic and Linear Vla Antagonists of AVP

Pept ide

Antivasooressor Antiantidiuretic

€0 EDa pA, ED' PA,^ Ratio'

d(CH2),VOAVPd 1.5 7.68 agonist

d( CH,), [Tyr (Me)2] AVPe 0.16 8.62 agonist

d(CH2), [Tyr(He)2. EOA'] AVPf 0.12 8.75 mixed - 33 - 6.3 - 275 d(CH2),[Tyr(Me)'.Ala-NH~]AVPf 0.13 8.75 mixed - 77 - 6.0 - 590 d(CH2), [Tyr(Me)2. Arg-NH:] AVP' 0.12 8.78 mixed - 18 - 6.6 - 150 Aaa-0-Tyr (Et ) -Phe-Va l-Asn-Arg-NHZg 0.72 7.98 43 6.20 60 Phaa-0-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH,; 0.07 9.05 mixed - 40 - 6.3 - 570 Phaa-0-Tyr(Me)-Phe-Gln-Asn-Lys-Pro-Arg-NH, 0.08 8.93 > 24 < 6.5 > 290 Phaa-0-Tyr(Me) -Phe-Gln-Asn-Lys-Pro-Arg-Tyr-NHZi 0.22 8.50 agonist

Phaa-0-Tyr(Me) -Phe-G ln-Asn-Arg-Pro-Arg-Tyr-NH2i 0.08 8.94 agon i st

a*bSee corresponding footnotes Table 2. CfEO ratio: antiantidiuretic EO/antivasopl;essor €0. dData franref. 42. %ata fran ref. 22. Data fran ref. 23. gOata from ref. 41. Data fran ref. 25. 'Data fran ref . 43. EOA = ethylenediamine. Phaa = phenylacetyl. Aaa = adamantaneacetyl.

(0.10 U / q )

(0.31 U/w)

(0.020 U/mg)

(0.042 Ulmg)

1 2 3 4 5 6 7 8 9 -Asn-C -Pro-0-Arg-Gly-NH, r

S

d (CH,),VDAVP

was found t o be a weak p a r t i a l V, agonist and t o be a much more potent V,, antagonist than dVDAVP (42) (Table 3 ) . T h i s f i nd ing focused our e f f o r t s on the design o f V,, antagonists. Using the cyclopentamethylene [(CH,),] subs t i t u t i on a t pos i t i on one and t h e Tyr(Me) subs t i t u t i on a t p o s i t i o n two i n the potent V,/V,, agonist dAVP l e d t o one o f the most potent and s e l e c t i v e V,, antagonists yet reported: d(CH,),Tyr(Me)AVP (22). Th is has become one o f the most widely used AVP V,, antagonists (10,12) . Further modif icat ions o f d(CH,),Tyr(Me)AVP a t p o s i t i o n nine have resu l ted i n potent V,, antagonists w i t h g r e a t l y diminished V, agonism (Table 3) ( 2 3 ) .

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TABLE 4 . AVP V,,/Vlb Antagonists

Antivasopressor ( A n t i - V : , l Ant id iure t ic

Anti-ACTH Pept ide PA; Wm9 Release (Anti-V,,)

dP [Tyr(Me)']AVPC 7.96 3.5 K~ = 3.3 nmolee dP [Tyr (Me)', A la-NH;] AVPd 8.16 0.040 dP [Tyr ( Me)',Tyr-NH2]AVPd 8.25 0.029 dP [Tyr ( Me)2.Arg-NH2] AVPd 8.52 0.083

,See corresponding footnote Table 2. 'Data from r e f . 24. dData from r e f . 23. eOata from r e f s . 45, 46. dP = deaminopenicillamine.

Desiqn of AVP V,, antaqonists (Table 4)

The most potent V,, antagonist reported to date is [l-deaminopenicillamine, 2-0-methyltyrosine] arginine vasopressin(dPTyr(Me)- AVP) (24). It has the following structure:

1 2 3 4 5 6 7 8 9 CH,-CO-Tyr(Me)-Phe-Gln-Asn-Cy-Pro-Arg-Gly-NH2

I S

dPTyr(Me)AVP

This was designed and synthesized as a V,, antagonist and is in fact a potent V,, antagonist (24). It was later shown to be also a V,, antagonist (45,46). It thus represents a promising lead for the design of AVP V,, antagonists. In this regard, some of the nine- substituted analogs of dPTyr(Me)AVP in Table 4 (23) are a l so likely candidates as V,, antagonists. Use of the aforementioned D-3- (pyridy1)-alanine (15) at position two in dPTyr(Me)AVP might also lead to a V,, antagonist.

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TABLE 5. Non-Selective Cycl ic and Linear AVP V2/Vla Antagonists

Ant iant i d iu re t i c Antivasopressor (Ant i - V , L fAnti-V:)

ED Peptide PA,a PA,’ Ratiob

d(CH2)5 [Tyr (Et )2, Va 14, 0- Arg? VPCId 7.10 8.31 0.06 d(CH2)5[Tyr(Et)2.Va14]AVPc 7.57 8.16 0.3 d(CH2)5 [D-Tyr(Et )‘,Va14]AVPe 7.81 8.22 0.3 desGlyd( CHZIS [D-Tyr ( Et),. Va 14] AVPe 7.69 8.17 0.3 Aaa-D-Tyr( E t ) -Phe-Va l-Asn-Abu-Pro-Arg-Arg-NHZf 8.11 7.75 2.3 Phaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2e 7.99 8.42 0.4 t-Baa-0-Tyr( Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH: 7.91 7.99 0.9

corresponding footnotes t o Table 2. ‘Data from ref. 27. fdThis i s a lso a potent OT eData frm r e f . 10. Data from r e f . 28. Aaa = antagonist ( i n v ivo) anti-0T PA, = 8.19.

adamantaneacetyl: Phaa = phenylacetyl; t-Baa = te r t -bu ty lace ty l .

Desiqn of cyclic AVP V2&,, antaqonists (Table 5)

It was not until 1981, almost 30 years after the first laboratory synthesis of oxytocin (5), that the first AVP V, antagonists were reported (26,27). Modi f i cat i on of the aforementioned V,, antagonist/weak partial V, agonist d(CH,),VDAVP (42) by incorporation of Tyr(Me) or Tyr(Et) at position two proved to be the final piece in the molecular design puzzle which had teased investigators in many laboratories over this period. Thus one of the first four V,/V,, antagonists, d(CH,),Tyr(Et)VDAVP (26) (Table 5) has the following structure:

1 2 3 4 5 6 7 8 9 - CO -Tyr ( Et ) - Phe - Val - Asn - Cy - Pro - D- Arg - G1 y - NH,

I S

d(CH,),Tyr (Et)VDAVP

This discovery opened the door to the design of a wide variety of AVP V2/Vla antagonists possessing significant enhancements in anti-V,

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TABLE 6. Selective Cyclic and Linear AVP V2 Antagonists

Antiantidiuretic Antivasopressor (Anti-V,] (Anti-V:)'

€0 Peptide ED' pA: ED' pA: Ratio'

d( CH2)5 [D- I le2, I le4] AVPd 0.67 8.04 26 6.42 39 desG 1 yNH,d(CH l5 [0- I le', I le4] AVPd 0.90 7.88 - 400 - 5 . 2 - 400 d(CH2)5[D-I 12, I le4.Ala-NH2]AVPd 0.46 8.16 38 6.25 83 Pa-O-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2e I . 3 7.74 14 6.71 12 Pa-0-Tyr( E t ) -Phe-Va l-Asn-Nva-Pro-Arg-Arg-NH,e 0.60 8.07 13 6.73 22

aJbSee corresponding footnotes Table 2. dData fran ref. 1 0 . eOata from r e f . 13. Pa = propionyl. Nva = norvaline.

'ED ratio = antivasopressor ED/antiantidiuretic ED.

potency (10) (Table 5) and anti-V,/anti-V,, s e l e c t i v i t y (10) (Table

6). Changes a t pos i t i ons two (D-Tyr(Et), D-Phe) and e i g h t (L-Arg) were found t o be p a r t i c u l a r l y use fu l i n improving anti-V, potency (10). U t i l i z i n g leads from our l abo ra to ry o thers have made very important con t r i bu t i ons t o the design o f po ten t V, antagonists

(9,361 *

Desiqn o f se lec t i ve AVP V, an tason is ts (Table 6 1

A l l o f the e a r l y AVP V, antagonists were a l so potent V,, antagonists (27) . I n f a c t they were a l l more po ten t as V,, antagonists than as V, antagonists. However mod i f i ca t i ons o f one the f i r s t non-sel ec t i v e V,/V,, antagoni s ts , d(CH,),Tyr( E t )VAVP (Tab1 e 5) a t pos i t i ons 2, 4 and 9 l e d t o one o f t he most po ten t and se lec t i ve V, antagonists repor ted t o date, d(CH,),[D-Ile', I le4 ,A la - NH;]AVP (10). It has the f o l l o w i n g s t ruc tu re :

1 2 3 4 5 6 7 8 9 /CH,-CO-D- I 1 e-Phe- I 1 e-Asn-Cy-Pro-Arg-A1 a-NH,

I S

d (CH,) [ D- I 1 e2, I 1 e4, A1 a-NH;]AVP

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I t s propert ies, together w i t h those o f some re la ted se lec t i ve AVP V, antagonists are given i n Table 6 . A number o f these pept ides have and are being widely used i n studies aimed a t determining which AVP receptor subtypes mediate d i f f e r e n t responses t o AVP.

Discoverv o f l i n e a r V,& antaaonists

This was a d e l i g h t f u l surpr ise. The e a r l y l i n e a r antagonists (28) were der ived from the l i n e a r precursor o f the c y c l i c V2/Vla antagonist d(CH,),D-Tyr(Et)VAVP (Table 4) . This precursor has t h e fo l l ow ing s t ruc tu re :

1 2 3 4 5 6 7 8 9 ,CH,-CO-D-Tyr( E t ) -Phe-Val -Am-Cy-Pro-Arg-Gly-NH, (A)

I SH

This was shown t o possess - 1/5 t he V, and V,, an tagon is t i c potencies o f t he cyc l i zed d(CH,),D-Tyr(Et)VAVP (28). Modi f i ca t ions a t pos i t i ons 1, 6 and 9 t o g i ve t h e l i n e a r pept ide (8) (Table 5) brought about s i g n i f i c a n t enhancements i n both V, and V,, antagon is t i c potencies (28,43).

1 2 3 4 5 6 7 8 9 Aaa-D-Tyr(Et) -Phe-Val -Am-Abu-Pro-Arg-Arg-NH, (8)

Aaa = adamantaneacetyl

Further mod i f i ca t ions o f (8) a t pos i t i ons 1 and 6 l e d t o the more se lec t i ve l i n e a r V, antagonist C (Table 6 ) .

1 2 3 4 5 6 7 8 9 Pa-D-Tyr( Et)-Phe-Val -Am-Nva-Pro-Arg-Arg-NH, ( C )

Pa = propionyl ; Nva = norval i ne

Desian o f se lec t i ve l i n e a r V,- antaaonists (Table 3)

One o f t he most potent and se lec t i ve l i n e a r V,, antagonists t o date (25) has the fo l l ow ing s t ruc tu re :

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TABLE 7 . Radiolabelled Ligands f o r Vasopressin and Oxytocin Receptors

Oissociat ion Constants (nH) f o r Binding t o Receutors from:

Rat Rat Rat Rat Kidney L i v e r Hypophysis Uterus

Radio labe 1 led L iganda (V,) (Vl.9) (‘lh) (01)

r3H] -AVP 0.4 0.6 - 3 1 - 3 1.7 [3H] -LVP 7 8 4 1.7 [3H] -0T 370 78 250 1.0 - 2.5 [3H] - [Thr4,Gly7] OT > 10,000 > 8,000 1 [3H]desGly9-d(CH2)5- [D-Tyr( E t )‘I VAVP 0.4 0.2 [3H]desGly-NH~d(CH ) [O-Ile2. Ile4]AVPb 2.8 [3H]-d(CH2),- [Tyr(Me) 2 1 I A V P 0.3 E3H]d0AVP 0.8

13.6 0.03 [ 125 I] -d(CH2I5- [Tyr(Me)2-Thr4-Tyr(NH2)9] OVT [12’1] d(CH2)5- [Tyr(Me)2-Tyr(NH2)9]AVP 1.0 0.28 0.13 [1251] -d(CH2)5[Sar7]AVP 3.0 [1251]Phaa-O-Tyr(He)-Phe-Gln-Asn-Arg-Pro-Arg- 62 0.06 92 1.4

10.2

Tvr-NH,

‘For references see r e f . 32. bReported i n r e f . 29.

1 2 3 4 5 6 7 8 Phaa-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (D)

Phaa = Phenylacetyl

This was designed by replacing Aaa’ and Val4 in the desArg9 analog o f (B) with Phaa’ and Gin4 respectively. Its properties are given in Table 3.

Desiqn o f non-selective linear OT antaqonist (Table 21

1 2 3 4 5 6 7 8 9 Aaa-D-Tyr(Et) -Phe-Val -Asn-Abu-Pro-Arg-Gly-NH, (E)

This was designed (28,41) by replacing the position 1 and 6 substituents o f (A) with Aaa and Abu respectively. It is a more potent V2/Vla antagonist than an OT antagonist. Nonetheless, it represents a promising lead to linear OT antagonists.

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Desiqn o f AVP and OT receDtor radiol iaands (Table 7 1

Radiolabeled l igands can be powerful t oo l s f o r receptor

l oca l i za t i on and i d e n t i f i c a t i o n (12). Although t r i t i a t e d OT i s spec i f i c f o r OT receptors, t r i t i a t e d AVP and LVP lack s p e c i f i c i t y f o r any given VP receptor. Thus t r i t i a t e d VPs bind t o V,, V,,, V,, and OT receptors. T r i t i a t i o n o f the se lect ive OT agonist [Thr4,Gly7]0T and o f the se lect ive V, agonist dDAVP resul ted i n radioligands wi th enhanced s e l e c t i v i t y f o r OT (30) and V, (31) receptors respect ively. T r i t i a t i o n o f the se lect ive AVP V,,

antagonist, d(CH,),Tyr(Me)AVP and the se lect ive V, antagonist desGlyNH,,d(CH,),[D-Ile', Ile'IAVP also resul ted i n l abe l l ed peptides which are h igh ly select ive f o r V,, and V, receptors respect ively [ f o r references see (32)].

Radioiodinated 1 igands o f f e r s i g n i f i c a n t advantages over t r i t i a t e d peptides. They are easier and less expensive t o prepare. Also they possess much higher spec i f i c r a d i o a c t i v i t i e s which can improve the s e n s i t i v i t y and accuracy o f receptor binding studies. Furthermore rad io iod inat ion permits much more rap id and d e f i n i t i v e radioautographic l oca l i za t i on o f receptors. Thus the development o f good radioiodinated l igands f o r OT, V,,, V, and V,, receptors have been long-standing goals as too l s f o r studies on these receptors. Table 7 l i s t s some o f the t r i t i a t e d and radioiodinated l igands which have been designed t o date. I n co l laborat ion wi th Serge Jard,

Claude Barberis and colleagues i n Montpell ier, France, we have designed two h igh ly promising radioiodinated 1 igands f o r OT and V,, receptors. One i s based on a c y c l i c OT antagonist the other on a l i n e a r AVP V,, antagonist. The OT l igand i s ['251]d(CH,)5- [Tyr(Me)',Thr4,Tyr-NH;]0VT (20). The V,, l igand i s : ['251]Phaa-D- Tyr(Me)Phe-G1 n-Asn-Arg-Pro-Arg-Tyr(NH,) (32) (Table 7). These were designed by incorporating a C-terminal Tyr-NH, i n t o a potent OT antagonist and a potent V,, antagonist respectively. While the

search f o r select ive high a f f i n i t y radioiodinated l igands f o r V, and V,, receptors has so f a r been unsuccessful, we are hopeful t h a t new approaches w i l l lead t o these e lus ive goals.

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Uses o f AVP and OT se lec t i ve aoonists and antaoonists

Se lec t i ve agonists and antagonists f o r OT, V,,, V,, and V, receptors have found widespread uses i n s tud ies aimed a t understanding the biochemical, phys io log ica l neurotransmit ter , pharmacological and pathophysiological r o l e s o f these pept ides (10,12). L i t e r a l l y hundreds o f s tud ies have been c a r r i e d ou t i n 1 aborator ies worldwide and hundreds o f pub1 i c a t i o n s have resu l ted

from s tud ies c a r r i e d ou t w i t h s e l e c t i v e agonists and antagonists

dur ing the past decade (10,12). Space l i m i t a t i o n s do no t permit more than a very b r i e f l i s t i n g o f t he types o f s tud ies which have been c a r r i e d ou t w i t h these peptides. These s tud ies f a l l i n t o the f o l 1 owing general categor ies :

1.

2.

3 .

4.

5 .

6 . 7.

The use o f rad io l igands and p h o t o a f f i n i t y l igands f o r the l o c a l i z a t i o n and i d e n t i f i c a t i o n o f OT and AVP receptor subtypes. The cha rac te r i za t i on o f receptor subtypes w i t h non-1 abel l e d se lec t i ve agonists and antagonists. The r o l e o f AVP i n per iphera l and cen t ra l con t ro l o f b lood pressure. The r o l e o f AVP i n the r e g u l a t i o n o f f ree-water r e t e n t i o n by the kidney.

The r o l e o f AVP and OT on behavior and i n memory and 1 earning. The r o l e of AVP and OT i n the re lease o f ACTH. The r o l e o f AVP i n pros tag land in and s t e r o i d biosynthesis.

TheraDeutic uses o f AVP aqonists and antaqonists

dDAVP (33) has long been the drug o f choice f o r t he t reatment o f diabetes i ns ip idus . OT i s w ide ly used f o r t h e i nduc t i on o f l a b o r ( 4 ) . OT antagonists have therapeut ic p o t e n t i a l f o r the i n h i b i t i o n o f premature l abo r (4,10,12). One such an tagon is t i s now undergoing c l i n i c a l t r i a l (34) and o thers c u r r e n t l y being developed a t Merck (18) may soon be tested. The V,, antagonist, d(CH,),Tyr(Me)AVP (22)

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i s e f fec t i ve i n man (35) but as o f now, does not have any therapeutic indicat ions. A safe and e f f e c t i v e V, antagonist could be o f therapeutic value f o r the treatment o f excessive water re tent ion and d i l u t i o n a l hyponatremia (26). O f the hundreds o f c y c l i c and l i n e a r V,/V,, antagonists synthesized t o date, only t w o have been tested i n human volunteers. Both were found t o behave as agonists (36). I t i s hoped t h a t one o r more o f the known V, antagonists o r o f the peptide V, antagonists cu r ren t l y on the

drawing board o r one o f the recent ly reported non-peptide V, antagonists (17) w i l l behave as V, antagonists i n humans and w i l l thus be o f value f o r the treatment o f water re tent ion due t o inappropriate vasopressin secretion.

ACKNOWLEDGEMENTS

Work from the authors' laborator ies was supported i n pa r t by research grants from the National I n s t i t u t e o f General Medical Sciences (GM-25280) and the National I n s t i t u t e o f Diabetes and Digestive and Kidney Disease (DK-01940). We are indebted t o a l l our co-workers who have par t ic ipated i n these studies. We also wish t o thank Ms. Ann Chlebowski f o r her expert assistance i n the preparation o f t h i s manuscript.

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Lammek, B.; Bankowski, K.; Misicka, A.; Manning, M.; Seto, J . ; and Sawyer, W.H. 2 -0 -a l ky l - t y ros ine de r i va t i ves o f l-deamino- a rg in ine vasopressin: h i g h l y s p e c i f i c and potent a n t i d i u r e t i c agonists. J. Med. Chem. 32, 244-247, 1989.

Lowbridge, J.; Manning, M.; Seto, J . ; Haldar, J.; and Sawyer, W.H. Synthet ic antagonists o f i n v ivo responses by the r a t uterus t o oxytocin. J. Med. Chem. 22, 565-569, 1979.

Bankowski, K.; Manning, M.; Seto, J . ; Haldar, J . ; and Sawyer, W.H. Design and synthesis o f potent i n v i vo antagonists o f oxytocin. I n t . J. Pept. P ro te in Res. 16, 382-391, 1980.

Manning, M.; Kruszynski, M.; Bankowski, K.; Olma, A.; Lammek, B.; Cheng, L.L.; K l i s , W.A.; Seto, J.; Haldar, J.; and Sawyer, W.H. So l i d phase synthesis o f 16 potent ( se lec t i ve and nonselective) i n v ivo antagonists o f oxytocin. J. Med. Chem.

Manning, M.; K l i s , W.A.; Przybylski , J.; Kruszynski, M.; Olma, A., Bankowski, K.; Lammek, B.; Wo, N.C.; and Sawyer, W.H. Linear antagonists o f a rg in ine vasopressin and oxytocin. I n Peptides, ed i ted by Jung, G.; and Bayer, E., p. 552-555, Be r l i n : Walter de Gruyter, 1989.

Lowbridge, J.; Manning, M.; Haldar, J ; and Sawyer, W.H. [l-j- mercapto- j , j -cycl opentamethyl enepropanoi c acid, 4-val i ne, 8-D- arg in ine ] vasopressin, a potent and se lec t i ve i n h i b i t o r o f t he vasopressor response t o a rg in ine vasopressin. J. Med. Chem.

Manning, M.; K l i s , W.A.; Przybylski , J.P.; Kruszynski, M.; Olma, A.; Wo, N.C.; Pelton, G.H.; and Sawyer, W.H. Novel 1 inear antagonists o f t he a n t i d i u r e t i c (V,) and vasopressor ( V ) responses t o vasopressin. I n t . J. Pept. Pro te in Res. 32, 455-467, 1988.

Manning, M.; Kolodziejczyk, A.S.; Stoev, S.; K l i s , W.A.; Wob N.C.; and Sawyer, W.H. H igh ly potent and se lec t i ve Tyr-NH, containing l i n e a r V, antagonists; D-Tyr2-containing 1 inear Vz- antagonists: po ten t i a l rad io iod ina ted 1 igands f o r vasopressin receptors. I n Peptides 1990: Proc. 21st fur. Pep. Symp., ed i ted by G i r a l t , E.; and Andreu, D., p. 665-667, ESCOM, Leiden, 1990.

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21, 313-315, 1978.

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45. Antoni, F.A. Novel ligand specificity o f pituitary vasopressin receptors in the rat. Neuroendocrinology 39, 186-188, 1984.

46. Rivier, C . ; Rivier, J.; Mormede, P.; and Vale, W . Studies of the nature of the interaction between vasopressin and corticotropin-releasing factor on adrenocorticotropin release in the rat. Endocrinology 115, 882-886, 1984.

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design, synthesis and some uses of receptor-specific agonists and antagonists of vasopressin and...

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