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Synthesis and pharmacological evaluation of benzamide derivatives as selective 5-HT(4) receptor agonists
Shuji Sonda1, Toshio Kawahara, Kenichi Katayama
1Pharmaceutical 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
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.
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