Synthesis and Evaluation of Novel 2-Oxo-1, 2-dihydro-3-quinolinecarboxamide Derivatives as Potent and Selective Serotonin 5-HT4 Receptor Agonists

• Published in: Chemical & pharmaceutical bulletin Vol. 49; no. 1; pp. 29 - 39
• Main Authors: SUZUKI, Masaji, OHUCHI, Yutaka, ASANUMA, Hajime, KANEKO, Toshie, YOKOMORI, Sadakazu, ITO, Chika, ISOBE, Yoshihiko, MURAMATSU, Makoto
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 2001; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Animals; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Digestive system; Dogs; Drug Evaluation, Preclinical; Female; Gastrointestinal Motility - drug effects; Life Sciences & Biomedicine; Male; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; quinolinecarboxamide; Quinolines - chemical synthesis; Quinolines - pharmacology; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT4; Science & Technology; serotonin 5-HT4 receptor agonist; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - pharmacology; Spectrum Analysis; structure-activity relationship; TS-951; CISAPRIDE; TS-951; serotonin 5-HT4 receptor agonist; GASTROINTESTINAL MOTILITY; quinolinecarboxamide; structure-activity relationship; Endo stereoisomer; Agonist; 5-HT4 Serotonine receptor; Motility; Nitrogen heterocycle; Lactam; Smooth muscle; Selectivity; Gastrointestinal; Dose activity relation; Guinea pig; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Dog; Fissipedia; Stimulant; Carnivora; Digestive system; Rodentia; Oral administration; Quinoline derivatives; Gastric emptying; Ileum; In vitro; In vivo; Vertebrata; Mammalia; Animal; Carboxamide
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.49.29

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 althought 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.