Pharmacological characterization of RWJ-676070, a dual vasopressin V(1A)/V(2) receptor antagonist

Eur J Pharmacol. 2008 Aug 20;590(1-3):333-42. doi: 10.1016/j.ejphar.2008.06.010. Epub 2008 Jun 7.


The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V(1A) and V(2) receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V(1A) and V(2) receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V(1A), V(1B) or V(2) receptors. Its inhibition of V(1A) receptor-mediated contraction of vascular rings and platelet aggregation was determined. V(2) receptor-medated aquaresis was determined in rats, dogs and monkeys. V(1A) 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 V(1A) and V(2) receptors (Ki=1 and 14 nM, respectively). RWJ-676070 inhibited V(1A) receptor-induced intracellular calcium mobilization and V(2) receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V(1A) receptors. RWJ-676070 inhibited V(1A) 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 V(1A) and V(2) receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V(1A) and V(2) receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Benzazepines / pharmacology*
  • Blood Pressure / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Heart Rate / drug effects
  • Humans
  • Hypertension / drug therapy
  • In Vitro Techniques
  • Macaca fascicularis
  • Male
  • Platelet Aggregation / drug effects
  • Rats
  • Rats, Inbred SHR
  • Spiro Compounds / pharmacology*
  • Vasoconstriction
  • Vasopressins / pharmacology


  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • RWJ-676070
  • Spiro Compounds
  • Vasopressins