OPC-41061, a highly potent human vasopressin V-2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosingin rats

The pharmacological profile and the acute and chronic aquaretic effects of OPC-41061, a novel nonpeptide human arginine vasopressin (AVP) V-2-receptor antagonist, were respectively characterized in HeLa cells expressing clone d human AVP receptors and in conscious male rats. OPC-41061 antagonized [H- 3]-AVP binding to human V-2-receptors (K-i = 0.43 +/- 0.06 nM) more potentl y than AVP (K-i = 0.78 +/- 0.08 nM) or OPC-31260 (K-i = 9.42 +/- 0.90 nM). OPC-41061 also inhibited [H-3]-AVP binding to human V-1a-receptors (K-i = 1 2.3 +/- 0.8 nM) but not to human V-1b-receptors, indicating that OPC-41061 was 29 times more selective for V-2-receptors than for V-1a- receptors. OPC -41061 inhibited cAMP production induced by AVP with no intrinsic agonist a ctivity. In rats, OPC-41061 inhibited [H-3]-AVP binding to V-1a-receptors ( K-i = 325 +/- 41 nM) and V-2-receptors (K-i = 1.33 +/- 0.30 nM), showing hi gher receptor selectivity (V-1a/V-2 = 244) than with human receptors. A sin gle oral administration of OPC-41061 in rats clearly produced dose-dependen t aquaresis. In treatment by multiple OPC-41061 dosing for 28 days at 1 and 10 mg/kg p.o. in rats, significant aquaretic effects were seen throughout the study period. As the result of aquaresis, hemoconcentration was seen at 4 hr postdosing although, no differences were seen in serum osmolality, so dium, creatinine and urea nitrogen concentrations at 24 hr postdosing. Furt hermore, there was no difference in serum AVP concentration, pituitary AVP content or the number and affinity of AVP receptors in the kidney and liver at trough throughout the study period. These results demonstrate that OPC- 41061 is a highly potent human AVP V-2-receptor antagonist and produces cle ar aquaresis after single and multiple dosing, suggesting the usefulness in the treatment of various water retaining states.