Suzuki M, Ohuchi Y, Asanuma H, Kaneko T, Yokomori S, Ito C, Isobe Y, Muramatsu M
Research Center Taisho Pharmaceutical Co., Ltd., Ohmiya, Saitama, Japan.
Chem Pharm Bull (Tokyo). 2001 Jan;49(1):29-39. 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 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.
合成了一系列8'-取代的N-(内-8-氮杂双环[3.2.1]辛-3-基)-1-异丙基-2-氧代-1,2-二氢-3-喹啉甲酰胺。使用离体豚鼠回肠标本评估5-HT4受体激动活性。在合成的化合物中，N-(内-8-(3-羟丙基)-8-氮杂双环[3.2.1]辛-3-基)-1-异丙基-2-氧代-1,2-二氢-3-喹啉甲酰胺(15a，TS-951)表现出最强的5-羟色胺5-HT4受体激动活性。该化合物对5-羟色胺5-HT4受体具有高亲和力，尽管它对其他广谱受体没有亲和力。此外，它能显著增强清醒进食犬的胃肠动力，且没有非选择性5-羟色胺5-HT4受体激动剂所具有的不良作用。TS-951可能对改善胃肠功能障碍有用。
