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Vol. 287, Issue 3, 860-867, December 1998
Second Tokushima Institute of New Drug Research (Y.Y., S.N., S.I.,
T.H., T.O., T.Y., Y.Y., K.T., M.A., H.O., H.Y., K.K., M.T., T.M.) and
Tokushima Research Institute (K.K.), Otsuka Pharmaceutical Company
Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan and
Department of Molecular Cell Pharmacology, National Children's Medical
Research Center (G.T.), 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan
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 (Ki = 0.43 ± 0.06 nM) more potently than AVP (Ki = 0.78 ± 0.08 nM) or OPC-31260 (Ki = 9.42 ± 0.90 nM). OPC-41061 also inhibited [3H]-AVP binding to human
V1a-receptors (Ki = 12.3 ± 0.8 nM) but not to human V1b-receptors, indicating that
OPC-41061 was 29 times more selective for V2-receptors than
for V1a-receptors. OPC-41061 inhibited cAMP production
induced by AVP with no intrinsic agonist activity. In rats, OPC-41061
inhibited [3H]-AVP binding to V1a-receptors
(Ki = 325 ± 41 nM) and V2-receptors (Ki = 1.33 ± 0.30 nM), showing higher receptor selectivity
(V1a/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.
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