Study on the clarification of molecular and pharmacological structure-activity relationships of 5-HT2A antagonists

5-HT2A拮抗剂分子及药理构效关系阐明的研究

• 批准号: 17590231
• 负责人: NAGATOMO Takafumi
• 金额: $ 2.58万
• 依托单位: Nigata University of Phermacy and Applied Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17590231/
• 关键词: 5-HT2A receptors; sarpogrelate; modeling; structure-activity relationships; inverse agonist; constitutively active; インバースアゴニスト; 5-HT_<2A>遮断薬; NMR; 5-HZ_2遮断薬; 5-HT_<2A>結合部位

Mutations producing constitutively active G-protein coupled receptors (GPCRs) have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT_<2A> receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT_<2A> receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT_<2A>-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT_<2A>-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT_<2A> receptor, we demonstrated that like other 5-HT_<2A>-receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate (IP) levels. However, there were no significant differences between sarpogrelate and other 5-HT_<2A>-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT_<2A> receptor may be a key component of the mechanism of action of sarpogrelate.

已经在几种疾病的病理生理学中发现产生组成型活性G蛋白偶联受体（GPCR）的突变，这意味着组成型活性受体的反向激动剂可能具有优选的治疗应用。由于5-HT_2受体参与<2A>了多种心血管疾病的发生和发展，因此，5-HT_2受体的组成性活性突变<2A>可能是导致心血管疾病的重要原因。因此，本研究的目的是研究选择性5-HT_<2A>-受体拮抗剂沙格雷酯及其活性代谢产物M-1的反向激动活性，并与其他5-HT_<2A>-受体拮抗剂如利坦色林、酮色林和赛庚啶的活性进行比较。利用人5-HT_2受体的组成型活性突变体（C322 K）<2A>，我们证明了沙格雷酯与其他5-HT_<2A>2受体拮抗剂一样，通过显著降低基础磷酸肌醇（IP）水平而作为一种有效的反向激动剂。然而，沙格雷酯与其他5-HT_<2A>-受体拮抗剂的反向激动活性无显著差异。与野生型受体相比，突变型受体对5-HT的亲和力显著提高，对沙格雷酯的亲和力显著降低。这些结果表明，稳定5-HT_2受体的非活性构象<2A>可能是沙格雷酯作用机制的关键组成部分。