Burrell L M, Phillips P A, Stephenson J M, Risvanis J, Johnston C I
University of Melbourne, Victoria, Australia.
Blood Press. 1994 Mar;3(1-2):137-41. doi: 10.3109/08037059409101533.
The development of nonpeptide orally active AVP analogues has provided a new tool with which to assess the physiological and pathophysiological role of vasopressin (AVP). We have previously characterised the nonpeptide vasopressin V1 receptor antagonist OPC-21268, and now report the in vitro characterisation of the nonpeptide V2 receptor antagonist OPC-31260 in the rat. OPC-31260 caused a concentration-dependent displacement of the selective AVP V2 receptor antagonist radioligand, [3H]desGly-NH2(9)[d(CH2)5, D-Ile2,Ile4]AVP from V2 receptors in rat kidney medulla membranes. The concentration of OPC-31260 that displaced 50% of specific AVP binding (IC50) was 20 +/- 2 nmol/l for renal V2 receptors. OPC-31260 also caused a concentration-dependent displacement of the selective AVP V1 receptor antagonist radioligand, [125I]-[d(CH2)5,sarcosine7]AVP from V1 receptors in both rat liver and kidney medulla membranes. The IC50 was 500 +/- 30 nmol/l for both renal and liver V1 receptors. After oral administration to rats, OPC-31260 was an effective inhibitor of AVP at renal V2 and liver V1 receptors in a time-dependent manner. In vitro binding kinetic studies showed that OPC-31260 was a competitive antagonist at both the renal V2 receptor and the hepatic V1 receptor. OPC-31260 is a nonpeptide, orally effective competitive inhibitor of AVP with a V2:V1 receptor selectivity ratio of 25:1 indicating relative V2 receptor selectivity.
非肽类口服活性抗利尿激素（AVP）类似物的研发为评估加压素（AVP）的生理和病理生理作用提供了一种新工具。我们之前已对非肽类加压素V1受体拮抗剂OPC - 21268进行了特性描述，现在报告非肽类V2受体拮抗剂OPC - 31260在大鼠体内的体外特性。OPC - 31260导致选择性AVP V2受体拮抗剂放射性配体[3H]去甘氨酰胺（9）[d（CH2）5，D - 异亮氨酸2，异亮氨酸4]AVP从大鼠肾髓质膜中的V2受体上呈浓度依赖性位移。使50%的特异性AVP结合被取代的OPC - 31260浓度（IC50），对于肾V2受体为20±2 nmol/L。OPC - 31260还导致选择性AVP V1受体拮抗剂放射性配体[125I]-[d（CH2）5，肌氨酸7]AVP从大鼠肝脏和肾髓质膜中的V1受体上呈浓度依赖性位移。肾和肝V1受体的IC50均为500±30 nmol/L。给大鼠口服后，OPC - 31260以时间依赖性方式有效抑制肾V2和肝V1受体处的AVP。体外结合动力学研究表明，OPC - 31260在肾V2受体和肝V1受体上均为竞争性拮抗剂。OPC - 31260是一种非肽类、口服有效的AVP竞争性抑制剂，V2:V1受体选择性比率为25:1，表明其对V2受体具有相对选择性。
