Abstract

The pharmacological profile and the acute and chronic aquaretic effects of OPC-41061, a novel nonpeptide human arginine vasopressin (AVP) V₂-receptor antagonist, were respectively characterized in HeLa cells expressing cloned human AVP receptors and in conscious male rats. OPC-41061 antagonized [³H]-AVP binding to human V₂-receptors (K_i = 0.43 ± 0.06 nM) more potently than AVP (K_i = 0.78 ± 0.08 nM) or OPC-31260 (K_i = 9.42 ± 0.90 nM). OPC-41061 also inhibited [³H]-AVP binding to human V_1a-receptors (K_i = 12.3 ± 0.8 nM) but not to human V_1b-receptors, indicating that OPC-41061 was 29 times more selective for V₂-receptors than for V_1a-receptors. OPC-41061 inhibited cAMP production induced by AVP with no intrinsic agonist activity. In rats, OPC-41061 inhibited [³H]-AVP binding to V_1a-receptors (K_i = 325 ± 41 nM) and V₂-receptors (K_i = 1.33 ± 0.30 nM), showing higher receptor selectivity (V_1a/V₂ = 244) than with human receptors. A single oral administration of OPC-41061 in rats clearly produced dose-dependent 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, sodium, creatinine and urea nitrogen concentrations at 24 hr postdosing. Furthermore, 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 V₂-receptor antagonist and produces clear aquaresis after single and multiple dosing, suggesting the usefulness in the treatment of various water retaining states.