Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

• Published in: Journal of peptide science 1997-01, Vol.3 (1), p.31-46
• Main Authors: Manning, Maurice, Cheng, Ling Ling, Stoev, Stoytcho, Klis, Wieslaw A., Nawrocka, Eleonora, Olma, Aleksandra, Sawyer, Wilbur H., Wo, Nga Ching, Chan, W. Y.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aic; Amino Acids - chemistry; Amino Acids - pharmacology; Animals; antagonist; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin - analogs & derivatives; Arginine Vasopressin - chemistry; Arginine Vasopressin - pharmacology; Atc; Biological Assay; Drug Design; Iodine Radioisotopes; Ligands; Oic; Peptides - chemistry; Peptides - pharmacology; Protein Conformation; Rats; receptor; Receptors, Vasopressin - agonists; Receptors, Vasopressin - chemistry; Structure-Activity Relationship; Tic; vasopressin
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/(SICI)1099-1387(199701)3:1<31::AID-PSC82>3.0.CO;2-Y

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 (V2‐receptor), vasopressor (V1a‐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(CH2)5D‐Tyr(Et) 2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid3 (Tic3) 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‐NH2 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 V2 and V1a assays and in in vitro (no Mg2+) n oxytocic assays. With the exception of the D‐Phe3 peptide (No. 6), which exhibits very weak V2 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 Pro3, Oic3, Tyr3, Trp3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr‐NH29 and D‐Cys6 substitutions in (B) are also well tolerated. The anti‐V2 pA2 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 pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti‐OT pA2 values ranging from 5.79 to 7.94. With an anti‐V2 potency of 7.77±0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti‐V2 pA2=7.81±0.07). These findings clearly indicate that position three in AVP V2/V1a 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 V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe