van Wijngaarden I, Kruse C G, van der Heyden J A, Tulp M T
Department of Medicinal Chemistry, Duphar Research Laboratories, Weesp, The Netherlands.
J Med Chem. 1988 Oct;31(10):1934-40. doi: 10.1021/jm00118a011.
A series of 2-phenylpyrrole Mannich bases was synthesized and screened in pharmacological models for antipsychotic activity and extrapyramidal effects. Structure modifications of 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (1), the prototype of a new class of sodium-independent atypical dopamine D-2 antagonists, resulted in 2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-5-(4-fluorophenyl)pyrrole (15), which was an even more potent and selective D-2 antagonist than the parent compound. The excellent oral activity in the apomorphine-induced climbing behavior and the conditioned avoidance response tests and the absence of catalepsy make this compound particularly promising as a potential antipsychotic with a low propensity to induce acute extrapyramidal side effects.
合成了一系列2-苯基吡咯曼尼希碱，并在药理学模型中筛选其抗精神病活性和锥体外系效应。新型非钠依赖性非典型多巴胺D-2拮抗剂的原型5-(4-氟苯基)-2-[[4-(2-甲氧基苯基)-1-哌嗪基]甲基]吡咯(1)的结构修饰产生了2-[[4-(7-苯并呋喃基)-1-哌嗪基]甲基]-5-(4-氟苯基)吡咯(15)，它是一种比母体化合物更有效和更具选择性的D-2拮抗剂。在阿扑吗啡诱导的攀爬行为和条件性回避反应试验中具有优异的口服活性且无僵住症，使得该化合物作为一种诱导急性锥体外系副作用倾向低的潜在抗精神病药物特别有前景。
