Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V_1A/V₂ receptor antagonist

Abstract

Pharmacology of conivaptan hydrochloride (YM087) was investigated in in vitro and in vivo studies. In radioligand binding study, YM087 showed high affinity for both V_1A and V₂ receptors in animal and human species. Affinity of YM087 for V_1A and V₂ receptors was comparable to that of vasopressin (AVP). In functional antagonistic activity study, YM087 concentration-dependently inhibited AVP-induced intracellular Ca²⁺ elevation via human V_1A receptors and AVP-stimulated cAMP accumulation via human V₂ receptors. Intravenous administration of YM087 dose-dependently inhibited AVP-induced pressor responses and produced a dose-dependent aquaresis in rats and dogs. Oral administration of YM087 showed a potent and long-lasting antagonistic activity on V_1A and V₂ receptors. YM087 was effective in dogs with heart failure and in heart failure rats with hyponatremia and edema. These results reveal that YM087 is the first orally active V_1A/V₂ receptor antagonist and suggest that YM087 may be useful in the treatment of congestive heart failure and hyponatremia.