NEW 5-HT3 (SEROTONIN-3) RECEPTOR ANTAGONISTS .4. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF AZABICYCLOALKANEACETAMIDE DERIVATIVES

The synthesis and structure-activity relationships of a series of new azabicycloalkanes as 5-HT3 (serotonin-3) receptor antagonists are desc ribed. Our study on the azabicycloalkaneacetamide derivatives showed t hat 2,3-dihydroindole as the aromatic ring moiety afforded potent 5-HT 3 receptor antagonist activity, as judged by blockade of bradycardia i nduced by i.v. injection of 2-methylserotonin in anesthetized rats. 7- Azaindole as the aromatic moiety afforded weak 5-HT3 receptor antagoni sts activity. The best 5-HT3 antagonists in this study were endo-3,3-d iethyl- (9k) and ethyl-2,3-dihydro-1-[(8-methyl-8-azabicyclo[3.2.1] oc t-3-yl)acetyl-1H-indole (9d), being approximately 10-fold more potent than ondansetron (1). This study shows that the azabicydoalkaneacetyl group is a new pharmacophoric element as a basic nitrogen and a linkin g carbonyl moiety.