Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamidederivatives as potent and selective serotonin 5-HT4 receptor agonists

A series of 8'-substituted N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl -2-oxo-1,2-dihydro-3-quinolinecar-boxamides were synthesized. The 5-HT4 rec eptor agonistic activity was evaluated using the isolated guinea pig ileum preparation. Of the compounds synthesized, N-(endo-8-(3-hydroxypropyl)-8-az abicyclo [3.2.1] oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinec (15a, TS-951) exhibited the most potent serotonin 5-HT4 receptor agonistic activ ity. This compound had a high affinity for the serotonin 5-HT4 receptor alt hough it had no affinities for other broad spectrum receptors, Furthermore, it remarkably enhanced gastrointestinal motility in conscious fed dogs wit hout unfavorable effects that non-selective serotonin 5-HT4 receptor agonis t has. TS-951 may be useful in improving gastrointestinal dysfunction.