OPC-41061, a highly potent human vasopressin V-2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosingin rats
Y. Yamamura et al., OPC-41061, a highly potent human vasopressin V-2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosingin rats, J PHARM EXP, 287(3), 1998, pp. 860-867
Citations number
40
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.