title: Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists.
abstract: A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized. The 5-HT4 receptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activity. This compound had a high affinity for the serotonin 5-HT4 receptor although it had no affinities for other broad spectrum receptors. Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs without unfavorable effects that non-selective serotonin 5-HT4 receptor agonist has. TS-951 may be useful in improving gastrointestinal dysfunction.
authors.affiliation: Research Center Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan. s13845@ccm.taisho.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Ohuchi
authors.forename: H
authors.initials: H
authors.lastname: Asanuma
authors.forename: T
authors.initials: T
authors.lastname: Kaneko
authors.forename: S
authors.initials: S
authors.lastname: Yokomori
authors.forename: C
authors.initials: C
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Isobe
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013057:Spectrum Analysis
chemical_list: D000577:Amides; D011804:Quinolines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4