Kato M, Ito K, Nishino S, Yamakuni H, Takasugi H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1995 Aug;43(8):1351-7. doi: 10.1248/cpb.43.1351.
The synthesis and structure-activity relationships of a series of new azabicycloalkanes as 5-HT3 (serotonin-3) receptor antagonists are described. Our study on the azabicycloalkaneacetamide derivatives showed that 2,3-dihydroindole as the aromatic ring moiety afforded potent 5-HT3 receptor antagonist activity, as judged by blockade of bradycardia induced by i.v. injection of 2-methylserotonin in anesthetized rats. 7-Azaindole as the aromatic moiety afforded weak 5-HT3 receptor antagonists activity. The best 5-HT3 antagonists in this study were endo-3,3-diethyl- (9k) and 3,3-dimethyl-2,3-dihydro-1-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl) acetyl-1H-indole (9d), being approximately 10-fold more potent than ondansetron (1). This study shows that the azabicycloalkaneacetyl group is a new pharmacophoric element as a basic nitrogen and a linking carbonyl moiety.
描述了一系列新型氮杂双环烷烃作为5-羟色胺3（5-HT3）受体拮抗剂的合成及其构效关系。我们对氮杂双环烷烃乙酰胺衍生物的研究表明，以2,3-二氢吲哚作为芳环部分可产生强效的5-HT3受体拮抗活性，这是通过在麻醉大鼠中静脉注射2-甲基5-羟色胺诱导的心动过缓的阻断来判断的。以7-氮杂吲哚作为芳环部分产生较弱的5-HT3受体拮抗活性。本研究中最佳的5-HT3拮抗剂是内型-3,3-二乙基-（9k）和3,3-二甲基-2,3-二氢-1-[(8-甲基-8-氮杂双环[3.2.1]辛-3-基）乙酰基]-1H-吲哚（9d），其效力比昂丹司琼（1）强约10倍。本研究表明，氮杂双环烷烃乙酰基作为一个碱性氮和一个连接羰基部分是一种新的药效基团元素。
