RT Journal Article
SR Electronic
T1 OPC-41061, a Highly Potent Human Vasopressin V<sub>2</sub>-Receptor Antagonist: Pharmacological Profile and Aquaretic Effect by Single and Multiple Oral Dosing in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 860
OP 867
VO 287
IS 3
A1 Yoshitaka Yamamura
A1 Shigeki Nakamura
A1 Shuji Itoh
A1 Takahiro Hirano
A1 Toshiyuki Onogawa
A1 Tatsuya Yamashita
A1 Yoshihisa Yamada
A1 Kenji Tsujimae
A1 Masashi Aoyama
A1 Kounori Kotosai
A1 Hidenori Ogawa
A1 Hiroshi Yamashita
A1 Kazumi Kondo
A1 Michiaki Tominaga
A1 Gozoh Tsujimoto
A1 Toyoki Mori
YR 1998
UL http://jpet.aspetjournals.org/content/287/3/860.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics