New 5-HT3 (serotonin-3) receptor antagonists. IV. Synthesis and structure-activity relationships of...

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.