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 (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.
Footnotes
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Send reprint requests to: Dr. Yoshitaka Yamamura, Otsuka Pharmaceutical Co., Ltd., 2-6-6 Awajimachi, Chuo-ku, Osaka 541-0047, Japan.
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↵1 This work was supported in part by research grants from Grant-in-Aid of the Japan Health Science Foundation, Tokyo, Japan.
- Abbreviations:
- AVP
- arginine vasopressin
- cAMP
- cyclic adenosine monophosphate
- BSA
- bovine serum albumin
- DMEM
- Dulbecco’s modified Eagle’s medium
- HeLa
- human endocervical carcinoma cells
- V1a-HeLa cells
- HeLa cells expressing human AVP V1a-receptors
- V1b-HeLa cells
- HeLa cells expressing human AVP V1b-receptors
- V2-HeLa cells
- HeLa cells expressing human AVP V2-receptors
- ANOVA
- analysis of variance
- CHF
- congestive heart failure
- Received March 27, 1998.
- Accepted June 25, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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