Nakamura S, Yamamura Y, Itoh S, Hirano T, Tsujimae K, Aoyama M, Kondo K, Ogawa H, Shinohara T, Kan K, Tanada Y, Teramoto S, Sumida T, Nakayama S, Sekiguchi K, Kambe T, Tsujimoto G, Mori T, Tominaga M
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., 463-10, Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
Br J Pharmacol. 2000 Apr;129(8):1700-6. doi: 10.1038/sj.bjp.0703221.
We discovered the first nonpeptide arginine-vasopressin (AVP) V(2)-receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V(2), V(1a) and V(1b)) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V(2)-receptor agonist. OPC-51803 and dDAVP displaced [(3)H]-AVP binding to human V(2)- and V(1a)-receptors with K(i) values of 91.9+/-10.8 nM (n = 6) and 3.12+/-0.38 nM (n = 6) for V(2)-receptors, and 819+/-39 nM (n = 6) and 41.5+/-9.9 nM (n = 6) for V(1a)-receptors, indicating that OPC-51803 was about nine times more selective for V(2)-receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [(3)H]-AVP binding to human V(1b)-receptors even at 10(-4) M, while dDAVP showed potent affinity to human V(1b)-receptors with the K(i) value of 13.7+/-3.2 nM (n = 4). OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V(2)-receptors with an EC(50) value of 189+/-14 nM (n = 6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V(2)-antagonist, OPC-31260. At 10(-5) M, OPC-51803 did not increase the intracellular Ca(2+) concentration (Ca(2+)) in HeLa cells expressing human V(1a)-receptors. On the other hand, dDAVP increased Ca(2+) in HeLa cells expressing human V(1a)- and V(1b)-receptors in a concentration-dependent fashion. From these results, OPC-51803 has been confirmed to be the first nonpeptide agonist for human AVP V(2)-receptors without agonistic activities for V(1a)- and V(1b)-receptors. OPC-51803 may be useful for the treatment of AVP-deficient pathophysiological states and as a tool for AVP researches.
我们发现了首个非肽类精氨酸加压素（AVP）V(2)受体激动剂OPC-51803。利用表达人AVP受体亚型（V(2)、V(1a)和V(1b)）的HeLa细胞阐明了OPC-51803的药理特性，并与肽类V(2)受体激动剂1-去氨基-8-D-精氨酸加压素（dDAVP）的药理特性进行了比较。OPC-51803和dDAVP使[(3)H]-AVP与人V(2)和V(1a)受体结合发生位移，对于V(2)受体，其K(i)值分别为91.9±10.8 nM（n = 6）和3.12±0.38 nM（n = 6），对于V(1a)受体，其K(i)值分别为819±39 nM（n = 6）和41.5±9.9 nM（n = 6），这表明OPC-51803对V(2)受体的选择性约为dDAVP的9倍。即使在10(-4) M时，OPC-51803也几乎不会使[(3)H]-AVP与人V(1b)受体的结合发生位移，而dDAVP对人V(1b)受体具有较强亲和力，其K(i)值为13.7±3.2 nM（n = 4）。OPC-51803在表达人V(2)受体的HeLa细胞中浓度依赖性地增加环磷酸腺苷（cAMP）生成，其EC(50)值为189±14 nM（n = 6）。在V(2)拮抗剂OPC-31260存在的情况下，OPC-51803诱导的cAMP生成浓度-反应曲线向右移动。在10(-5) M时，OPC-51803不会增加表达人V(1a)受体的HeLa细胞内的Ca(2+)浓度（[Ca(2+)]i）。另一方面，dDAVP以浓度依赖性方式增加表达人V(1a)和V(1b)受体的HeLa细胞内的[Ca(2+)]i。根据这些结果，已证实OPC-51803是首个对人AVP V(2)受体具有激动活性而对V(1a)和V(1b)受体无激动活性的非肽类激动剂。OPC-51803可能对治疗AVP缺乏的病理生理状态有用，并且可作为AVP研究的工具。
