Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, Yamada Y, Tsujimae K, Aoyama M, Kotosai K, Ogawa H, Yamashita H, Kondo K, Tominaga M, Tsujimoto G, Mori T
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Company Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
J Pharmacol Exp Ther. 1998 Dec;287(3):860-7.
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.
新型非肽类人精氨酸血管加压素（AVP）V2受体拮抗剂OPC - 41061的药理特性以及急性和慢性利水作用，分别在表达克隆人AVP受体的HeLa细胞和清醒雄性大鼠中进行了表征。OPC - 41061拮抗[3H]-AVP与人V2受体的结合（Ki = 0.43±0.06 nM），其效力比AVP（Ki = 0.78±0.08 nM）或OPC - 31260（Ki = 9.42±0.90 nM）更强。OPC - 41061还抑制[3H]-AVP与人V1a受体的结合（Ki = 12.3±0.8 nM），但不抑制与人V1b受体的结合，这表明OPC - 41061对V2受体的选择性比对V1a受体高29倍。OPC - 41061抑制AVP诱导的cAMP产生，且无内在激动剂活性。在大鼠中，OPC - 41061抑制[3H]-AVP与V1a受体（Ki = 325±41 nM）和V2受体（Ki = 1.33±0.30 nM）的结合，显示出比与人受体更高的受体选择性（V1a/V2 = 244）。在大鼠中单次口服OPC - 41061明显产生剂量依赖性利水作用。在大鼠中以1和10 mg/kg口服多次给予OPC - 41061进行28天治疗，在整个研究期间均观察到显著的利水作用。作为利水作用的结果，给药后4小时出现血液浓缩，尽管给药后24小时血清渗透压、钠、肌酐和尿素氮浓度没有差异。此外，在整个研究期间，谷值时血清AVP浓度、垂体AVP含量或肾脏和肝脏中AVP受体的数量和亲和力没有差异。这些结果表明，OPC - 41061是一种高效的人AVP V2受体拮抗剂，单次和多次给药后均产生明显的利水作用，提示其在治疗各种水潴留状态方面的有用性。
