Pharmacological characterization of RWJ-676070, a dual vasopressin V1A/V2 receptor antagonist

The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V1A and V2 receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V1A and V2 receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V1A, V1B or V2 receptors. Its inhibition of V1A receptor-mediated contraction of vascular rings and platelet aggregation was determined. V2 receptor-medated aquaresis was determined in rats, dogs and monkeys. V1A receptor-mediated inhibitory activity was assessed in vivo in a vasopressin-induced hypertension model and in normotensive rats and in two hypertensive rat models. RWJ-676070 inhibited AVP binding to human V1A and V2 receptors (Ki = 1 and 14 nM, respectively). RWJ-676070 inhibited V1A receptor-induced intracellular calcium mobilization and V2 receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V1A receptors. RWJ-676070 inhibited V1A receptor-mediated vasoconstriction in rat and dog vascular rings and AVP-induced human platelet aggregation. Dose dependent aquaresis was demonstrated in rats, dogs and monkeys following oral administration. RWJ-676070 inhibited AVP-induced hypertension in rats but had no effect on arterial pressure in normotensive and spontaneously hypertensive rats but did decrease arterial pressure in Dahl, salt-sensitive hypertensive rats. RWJ-676070 is a new, potent antagonist of V1A and V2 receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V1A and V2 receptors.