Gaster L M, Blaney F E, Davies S, Duckworth D M, Ham P, Jenkins S, Jennings A J, Joiner G F, King F D, Mulholland K R, Wyman P A, Hagan J J, Hatcher J, Jones B J, Middlemiss D N, Price G W, Riley G, Roberts C, Routledge C, Selkirk J, Slade P D
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park (North), Third Avenue, Harlow, Essex CM19 5AW, England.
J Med Chem. 1998 Apr 9;41(8):1218-35. doi: 10.1021/jm970457s.
5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.
5-羟色胺1（5-HT1）受体是G蛋白偶联受体超家族的成员，与腺苷酸环化酶活性呈负相关。人类5-HT1B和5-HT1D受体（以前分别称为5-HT1Dβ和5-HT1Dα），尽管由两个不同的基因编码，但结构上非常相似。在药理学上，这两种受体已通过使用非选择性化学工具（如酮色林和利坦色林）进行区分，但由于缺乏真正的选择性药物，这意味着5-HT1B和5-HT1D受体的确切功能尚未明确。在本文中，我们描述了如何以计算化学模型为指导，对非选择性5-HT1B/5-HT1D受体拮抗剂4进行结构修饰，以产生选择性5-HT1B受体反向激动剂5，即1'-甲基-5-[[2'-甲基-4'-(5-甲基-1,2,4-恶二唑-3-基)联苯-4-基]羰基]-2,3,6,7-四氢螺[furo[2,3-f]吲哚-3,4'-哌啶]（SB-224289）。该化合物在体外和体内都是终末5-HT自身受体功能的强效拮抗剂。
