King F D, Hadley M S, Joiner K T, Martin R T, Sanger G J, Smith D M, Smith G E, Smith P, Turner D H, Watts E A
SmithKline Beecham Pharmaceuticals, The Pinnacles, Harlow, Essex, U.K.
J Med Chem. 1993 Mar 19;36(6):683-9. doi: 10.1021/jm00058a004.
The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.
描述了含有氮杂双环[x.y.z]侧链的苯甲酰胺的合成及其5-HT4受体激动剂和5-HT3受体拮抗剂特性。这些化合物被设计用于模拟喹诺里西啶和吲哚里西啶的更高能量构象。尽管没有明显的完全平行的构效关系，但两种活性都实现了高效能。引入氧和硫仅导致效能上的微小差异，这在5-HT3拮抗作用中更为明显。在碱性氮的α位引入甲基导致5-HT4受体激动剂效能降低。确定了瑞扎普明（5f）进行进一步评估，其两种对映体具有相同的药理学特征，含两个单独对映体空间体积组合的氮杂三环9b也是如此。
