Synthesis and pharmacological evaluation of carboxamide derivatives as selective serotoninergic 5-HT4 receptor agonists (vol 34, pg 329, 1999)

A number of new carboxamide derivatives were synthesized. The affinity of t hese compounds for the serotoninergic 5-HT4 receptor was evaluated by use o f radioligand-binding techniques. The agonistic activity was evaluated as t he contractile effect of the ascending colon isolated from guinea-pigs. Amo ng these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[2-[(methylsulfonyl)ami no]ethyl]-4-piperidinylmethyl]benzamide (24) showed a high affinity for the 5-HT4 receptor (Ki = 9.6 nM). Compound 24 displayed a higher affinity for 5-HT4 receptors than the other receptors, including, 5-HT3 and dopamine D-2 receptors. In addition, compound 24 was confirmed to be a potent 5-HT4 rec eptor agonist (ED50 = 7.0 nM). An interaction model between compound 24 and 5-HT4 receptor was proposed. (C) 1999 Editions scientifiques et medicales Elsevier SAS.