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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 nMi), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10 microM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).

To investigate the anti-ulcer activity of the isoprenyl chalcone, sophoradin, which is present in a Chinese crude drug, Guang-dou-gen (the root of Sophora subprostrata), 30 related chalcones (1-30) were newly synthesized by condensation between substituted acetophenones and benzaldehydes, and their anti-ulcer activities were examined using Shay's pylorus-ligated rats, and water-immersed and restraint stress rats. Twenty-seven chalcones were substituted with isoprenyl or isoprenyloxyl groups and two with geranyloxyl groups (13, 30), with or without a carboxymethoxyl group, and one chalcone was substituted with allyloxyl group (14). All the chalcones were found to be effective by both methods. Several chalcones (2, 3, 8, 10, 11, 12, 15, 17, 22), each having more than one isoprenyloxyl group, exhibited high inhibitory ratios by both methods. In particular, 2', 4'-dihydroxy-3'-(3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy) chalcone (2), 2'-hydroxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (10), and 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone (15) exhibited very high inhibitory ratios (70-100%) by both methods, and were as potent as sophoradin.

Five dihydrochalcone derivatives, 2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) dihydrochalcone (M-6-b), 2', 4-bis (carboxymethoxy)-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-2), 2', 4-bis (carboxymethoxy)-4'-(3-carboxy-2-butenyloxy) dihydrochalcone (M-1-a), 2', 4-bis (carboxymethoxy)-4'-(3-hydroxymethyl-2-butenyloxy) dihydrochalcone (M-1-b), and 2'-carboxymethoxy-4-hydroxy-4'-(3-methyl-2-butenyloxy) dihydrochalcone (M-4-b), which are the main metabolites in rats of a new anti-ulcer drug "sofalcone"(2'-carboxymethoxy-4, 4'-bis (3-methyl-2-butenyloxy) chalcone) were synthesized and the anti-ulcer activities of the major metabolites in humans, M-6-b, M-2, and M-1-a, were examined by Shay's and Takagi's methods and also by the use of rats with histamine-induced ulcer. The most active compound was M-6-b, which showed activity equal to or slightly weaker than that of sofalcone.