Design of potent antagonists of the vasopressor response to arginine-vasopressin

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Abstract
As a part of a program attempting to design and synthesize antagonists of the vassopressor response to arginine-vasopressin (AVP), [1-deaminopenicillamine]arginine-vasopressin (dPAVP), [2-(O-methyl)tyrosine] arginine-vasopressin [Tyr(Me)AVP] and [1-deaminopenicillamine,2-(O-methyl)tyrosine]arginine-vasopressin [dPTyr(Me)AVP] were synthesized by the solid-phase method and assayed [using rats] for vasopressor, antidiuretic and oxytocic activities. Tyr(Me)AVP has a vasopressor potency of 9.7 .+-. 0.5 units[U]/mg and an antidiuretic potency of 386 .+-. 36 U/mg. These values are 2.5 and 120%, respectively, of the corresponding potencies of AVP. The analog is an antagonist of the in vitro response to oxytocin (pA2 = 7.44 .+-. 0.12). dPAVP has an antivasopressor pA2 of 7.45 .+-. 0.11. Its antidiuretic potency is 42.2 .+-. 2 U/mg, 2.5% that of its parent, 1-[deamino]arginine-vasopressin (dAVP). It is an antagonist of the in vitro response to oxytocin (pA2 value = 6.93 .+-. 0.10). dPTyr(Me)AVP has an antivasopressor pA2 of 7.96 .+-. 0.05 and an antidiuretic potency of 3.5 .+-. 0.5 U/mg. It is also an antagonist of the in vitro oxytocic response to oxytocin (pA2 value = 7.61 .+-. 0.14). It is thus one of the most potent vasopressor antagonists reported to date.

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