title: Synthesis and pharmacological evaluation of benzamide derivatives as selective 5-HT(4) receptor agonists.
abstract: It is thought that selective 5-HT(4) receptor agonists-such as 4-amino-5-chloro-2-methoxy-N-[1-(6-oxo-6-phenylhexyl)piperidin-4ylmethyl]benzamide (2)-have the ability to enhance both upper and lower gastrointestinal motility without any significant adverse effects. Modification of 2 was performed. Variation of the piperidin-4ylmethyl moiety of 2 led to a decrease in the binding affinity for the 5-HT(4) receptor. Following conversion of the carbonyl group on the benzoyl part to a hydroxyl or sulfoxide group, the binding affinity for the 5-HT(4) receptor was retained although the effect on defecation was reduced. Many of the 4-amino-5-chloro-2-methoxy-N-(piperidin-4ylmethyl)benzamides that had a ether or sulfide moiety in the side-chain part at the 1-position of the piperidine exhibited high affinity for the 5-HT(4) receptor. Among these, phenylthio 41c and benzylthio derivative 44 were selective 5-HT(4) receptor agonists, and had a similar effect on defecation to compound 2.
authors.affiliation: Pharmaceutical Development Laboratories, Technology and Production Division, Mitsubishi Pharma Corporation, 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki 314-0255, Japan. sonda.shuuji@ma.m-pharma.co.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Sonda
authors.forename: Toshio
authors.initials: T
authors.lastname: Kawahara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Katayama
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Asano
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists; D058828:Serotonin 5-HT4 Receptor Agonists
chemical_list: D001549:Benzamides; D017448:Receptors, Dopamine D2; D058828:Serotonin 5-HT4 Receptor Agonists