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

As part of a program in which we are attempting to design and synthesize antagonists of the vasopressor 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 for vasopressor, antidiuretic, and oxytocic activities. Tyr(Me)AVP has a vasopressor potency of 9.7 +/- 0.5 units/mg and an antidiuretic potency of 386 +/- 36 units/mg. These values are 2.5 and 120%, respectively, of the corresponding potencies of AVP. The analogue 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 units/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 units/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.