Synthesis and Structure-Activity Relationship of 3-Substituted Benzamide, Benzo[b]furan-7-carboxamide, 2, 3-Dihydrobenzo[b]furan-7-carboxamide, and Indole-5-carboxamide Derivatives as Selective Serotonin 5-HT₄ Receptor Agonists

Abstract

The title compounds (6-9) were prepared and evaluated for serotonin 5-HT₄ agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2, 3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2, 3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo-[3.3.0]octan-5-yl)ethyl]-5-chloro-2, 3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2, 3-dihydro-2, 3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D₁, D₂, serotonin 5-HT₁, 5-HT₂ and muscarine M₁, M₂ receptor binding activity in the in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.