5-Hydroxytryptamine (5-HT3) Receptor Antagonists. 1. Indazole and Indolizine-3-carboxylic Acid Derivatives

Article abstract of 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-a>pyridines 9 and 10, as potent 5-HT₃ receptor antagonists devoid ofeither 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.