Discovery of novel selective hypotensive vasopressin peptides that exhibit little or no functional interactions with known oxytocin/vasopressin receptors

Abstract

1 Arginine-vasopressin (VP) has both vasoconstricting and vasodilating action. We report here the discovery of four novel selective hypotensive VP analogues: d (CH 2 2 Bioassays in rats for activities characteristic of neurohypophysial peptides showed that the four VP peptides possessed little or no V 1a , V 2 or oxytocin (OT) receptor agonistic or antagonistic activities. 3 In anaesthetized rats, these peptides (0.05 ± 0.10 mg kg 71 i.v.) elicited a marked fall in arterial blood pressure. 4 Blockade of cholinoceptors, adrenoceptors and bradykinin B 2 receptors, and inhibition of prostaglandin synthesis had little e ect on their vasodepressor action. 5 Classical V 1a , V 2 and OT receptor antagonists did not block the vasodepressor response. 6 L-NAME, 0.2 mg kg 71 min 71 , markedly suppressed the hypotensive response to ACh but not the vasodepressor response to the hypotensive VP peptides. However, the duration of the vasodepressor response was shortened. Very high doses of L-NAME attenuated both the vasodepressor response and the duration of action. 7 These ®ndings indicate that the vasodepressor action of these VP peptides is independent of the peripheral autonomic, bradykinin and PG systems and is not mediated by the known classical OT/VP receptors. NO does not appear to have an important role in their vasodepressor action. 8 The discovery of these novel VP peptides could lead to the development of new tools for the investigation of the complex cardiovascular actions of VP and the introduction of a new class of hypotensive agents. The two iodinatable hypotensive VP peptides could be radiolabelled as potential markers for the localization of the receptor system involved. Keywords: Selective hypotensive vasopressin analogue agonists; hypotensive vasopressin peptides; nitric oxide and vasopressin analogues; vasodilating action of AVP) IntroductionArginine-vasopressin (AVP or VP) in addition to its well known antidiuretic action mediated by renal V 2 receptors, has also complex cardiovascular actions (Reid & Schwartz, 1984;Share, 1988). The systemic cardiovascular e ect of VP is peripheral vasoconstriction, leading to a rise in arterial blood pressure (Altura & Altura, 1977;Reid & Schwartz, 1984;Share, 1988). Regionally, VP can induce vasodilation (Liard, 1988;Naitoh et al., 1993;Nakanishi et al., 1995;Tagawa et al., 1995;van Lieburg et al., 1995). It also enhances the arterial barore¯ex, leading to a depression of heart rate and cardiac output (Cowley et al., 1984;Webb et al., 1986;Shimizu et al., 1993;Huch et al., 1995). It is now generally accepted that VP may play an important role in maintaining systemic blood pressure and in regulating regional blood¯ows during extreme hemodynamic alterations such as in a hypovolemic state (Schwartz & Reid, 1983;Landry et al., 1997;Reid, 1997). The vasopressor e ect of VP is mediated by V 1a receptors and the phosphatidylinositol-Ca 2+ signalling pathway (Michell et al., 1979;Jard et al., 1987). The barore¯ex e ect of VP appears to be mediated also by V 1a receptors (Webb...

Influence of 1‐aminocyclohexane‐1‐carboxylic acid in position 2 or 3 of AVP and its analogues on their pharmacological properties

“…The results suggested that position 3 is important not only for binding and recognition, but also for the intrinsic activity (14). In subsequent studies of other authors, Arg 3 /Phe 3 interchange in the nonselective antagonist mentioned above, [Cpa 1 , d ‐Tyr(Et) 2 , Val 4 ]AVP, resulted in a series of novel, selective hypotensive vasopressin analogues (15). Furthermore, another investigation of position 3 in AVP substituted with aliphatic, aromatic, conformationally restricted, polar and charged amino acids suggests that only thienylalanine (Thi) and aliphatic amino acids are well tolerated to give analogues with appreciable retention of activity (16).…”

Highly Potent 1-Aminocyclohexane-1-Carboxylic Acid Substituted V2Agonists of Arginine Vasopressin

“…More recent reports on such analogues resulted in inconsistent information, on one hand supporting the conclusion that this position is intolerant to structural modifications [5][6][7][8] and on the other hand demonstrating that Phe 3 could be replaced by a variety of amino acids with appreciable retention of activity. [7][8][9] In 1997 we described AVP analogues modified in position 3 with β-(1-naphthyl)-L-alanine. The results suggested that position 3 was important not only for binding and recognition but also for intrinsic activity.…”

“…Early findings demonstrating that aromatic Phe 3 is important for vasopressor activity, whereas aliphatic Ile 3 is crucial for oxytocic activity, probably influenced the design of neurohypophyseal hormone analogues because initially only a few studies were undertaken that involved substitutions in position 3 of AVP. More recent reports on such analogues resulted in inconsistent information, on one hand supporting the conclusion that this position is intolerant to structural modifications − and on the other hand demonstrating that Phe 3 could be replaced by a variety of amino acids with appreciable retention of activity. − In 1997 we described AVP analogues modified in position 3 with β-(1-naphthyl)- l -alanine. The results suggested that position 3 was important not only for binding and recognition but also for intrinsic activity .…”

Novel strategies for the design of receptor‐selective vasopressin analogues: Aib‐substitution and retro‐inverso transformation

“…The development of receptor‐selective analogues of neurohypophysial peptide hormones has facilitated the characterization of receptor subtypes and provided tools to address the diverse roles of these important peptide mediators. Moreover, the recent description of novel hypotensive vasopressin peptides (Chan et al ., 1998) and the development of chimeric vasopressin analogues (Howl et al ., 1997) indicate new avenues for structurally modified vasopressin analogues. Thus, modifications to improve receptor‐selectivity and/or stability and optimise pharmacodynamic and pharmacokinetic properties could enhance the utility and therapeutic potential of vasopressin/oxytocin analogues.…”