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

The title compounds (6-9) were prepared and evaluated for serotonin 5- HT4 agonistic activity in in vitro tests. Introducing a propyl or ally l group at the 3-position of benzamide caused only a slight enhancemen t of agonistic activity. Construction of the benzo[b]furan skeleton an d 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement o f the activity. thyl]-5-chloro-2-methylbenzo[b]furan-7-carboxamide (7b ) hemifumarate was as potent as cisapride. ro-2,3-dihydro-2-methylbenz o[b]furan-7-carboxamide (8a) hemifumarate, oro-2,3-dihydro-2-ethylbenz o[b]furan-7-carboxamide (8c) hemifumarate, and ,3-dihydro-2,3-dimethyl benzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than ci sapride. Furthermore, 8a hemifumarate was free from dopamine D-1, D-2, serotonin 5-HT1, 5-HT2 and muscarine M-1, M-2 receptor binding activi ty in the in vitro tests. On the other hand, construction of the indol e skeleton caused a remarkable decrease in activity.