Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor

A series of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT4) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT4 receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT4 receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC50 = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT3 receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT3 receptor antagonism on the colon were reduced compared with that of selective 5-HT4 receptor agonists. (C) 1999 Editions scientifiques et medicales Elsevier SAS.