[1-deaminopenicillamine,4-valine]-8-D-arginine-vasopressin, a highly potent inhibitor of the vasopressor response to arginine-vasopressin

In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.