Bermudez J, Fake C S, Joiner G F, Joiner K A, King F D, Miner W D, Sanger G J
Beecham Pharmaceuticals Research Division, Harlow, Essex, England.
J Med Chem. 1990 Jul;33(7):1924-9. doi: 10.1021/jm00169a016.
Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties. Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d and 8, and imidazo[1,5-alpha]pyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid of either dopamine antagonist or gastric motility stimulatory properties. Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial. From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.
甲氧氯普胺（1）是一种胃动力刺激剂，也是一种弱多巴胺和5 - HT3受体拮抗剂。以氮杂双环托烷形式对1的（二乙氨基）乙基侧链进行构象限制得到3，它是一种非常有效的胃动力刺激剂和5 - HT3受体拮抗剂，但没有明显的多巴胺受体拮抗剂特性。随后对芳环的改变导致鉴定出吲唑6a - h、1 - 和3 - 中氮茚7b - d和8以及咪唑并[1,5 - α]吡啶9和10，它们是有效的5 - HT3受体拮抗剂，既没有多巴胺拮抗剂特性也没有胃动力刺激特性。对侧链进一步的构象限制确定了奎宁环11和异奎宁环12为有效的5 - HT3受体拮抗剂，它们模拟了托烷的扭曲椅式构象，对于11而言，N - 甲基基团为轴向。从这些系列中，发现6g（BRL 43694）既有效又有选择性，并且已被证明是一种非常有效的抗呕吐剂，可对抗雪貂和人类中细胞毒性药物引起的呕吐。
