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

Abstract

A series of N-azabicycloalkyl-1-alkyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT₄ receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT₄ receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2-oxo-1, 2-dihydro-3-quinolinecarboxamide (8c, ED₅₀=36.3 nM), was seven times as active as cisapride, while 8c had no affinity for 5-HT_1A, 5-HT_1D, D₂, muscarinic M₂ or muscarinic M₃ receptors even at 10μM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).