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Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists
Author(s) -
Manning Maurice,
Cheng Ling Ling,
Stoev Stoytcho,
Klis Wieslaw A.,
Nawrocka Eleonora,
Olma Aleksandra,
Sawyer Wilbur H.,
Wo Nga Ching,
Chan W. Y.
Publication year - 1997
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(199701)3:1<31::aid-psc82>3.0.co;2-y
Subject(s) - chemistry , vasopressin , stereochemistry , antagonist , peptide synthesis , arginine , peptide , receptor , vasopressin antagonists , oxytocin , tyrosine , amino acid , biochemistry , endocrinology , biology
We report the solid‐phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1–12) of the potent non‐selective antagonist of the antidiuretic (V 2 ‐receptor), vasopressor (V 1a ‐receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT‐receptor) responses to oxytocin (OT), [1(‐β mercapto‐β,β‐pentamethy lenepropionic acid)‐2‐ O ‐ethyl‐ d ‐tyrosine 4‐valine] arginine vasopressin [d(CH 2 ) 5 D ‐Tyr(Et) 2 VAVP] (A) and two analogues of ( B ) (peptides 13,14), the 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid 3 (Tic 3 ) analogue of ( A ). Peptides 1–12 have the following substituents at position three in ( A ): (1) Pro; (2) Oic; (3) Atc; (4) D ‐Atc; (5) Aic; (6) D ‐Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr‐NH 2 9 analogue of ( B ): Peptide (14) is the D ‐Cys 6 analogue of ( B ). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V 2 and V 1a assays and in in vitro (no Mg 2+ ) n oxytocic assays. With the exception of the D ‐Phe 3 peptide (No. 6), which exhibits very weak V 2 agonism (…0.0017 u/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro 3 , Oic 3 , Tyr 3 , Trp 3 and Hphe 3 substitutions in ( A ) are very well tolerated, leading to excellent retention of V 2 , V 1a and OT antagonistic potencies. All are more potent as V 2 antagonists than the Ile 3 and Leu 3 analogues of ( A ). The Tyr‐NH 2 9 and D ‐Cys 6 substitutions in ( B ) are also well tolerated. The anti‐V 2 pA 2 values of peptides 1–5 and 7–14 are as follows (1) 7.77±0.03; (2) 7.41± 0.05; (3) 6.86±0.02; (4) 5.66±0.09; (5) …5.2; (7) 7.25± 0.08; (8) 6.82±0.06; (9) 7.58±0.05; (10) 7.61±0.08; (11) 7.59±0.07; (12) 7.20±0.05; (13) 7.57±0.1; (14) 7.52± 0.06. All analogues antagonize the vasopressor responses to AVP, with anti‐V 1a pA 2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti‐OT pA 2 values ranging from 5.79 to 7.94. With an anti‐V 2 potency of 7.77±0.03, the Pro 3 analogue of ( A ) is surprisingly equipotent with ( A ), (anti‐V 2 pA 2 =7.81±0.07). These findings clearly indicate that position three in AVP V 2 /V 1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V 2 antagonism exhibited by the Pro 3 , Oic 3 , Tyr 3 , Trp 3 and Hphe 3 analogues of ( A ), together with the excellent retention of V 2 antagonism by the Tyr‐NH 2 9 and D ‐Cys 6 analogues of ( B ) are promising new leads to the design of potent and possibly orally active V 2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH). © 1997 European Peptide Society and John Wiley & Sons, Ltd.