Treatment of 3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (13) with NaH–DMSO, and then reaction with 1,1-bis(2-methylphenyl)-4-bromobutane (12c) afforded 1-[4,4-bis(2-methylphenyl)butyl]-3-[2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (14). Reaction of methyl nicotinate with 2.1 equivalents 12c or 1,1-bis(2-methylphenyl)-4-bromo-1-butene (11b) afforded 4,4-bis(2-methylphenyl)butyl 1-[4,4-bis(2-methylphenyl)butyl]pyridinium-3-carboxylate bromide (17) or 4,4-bis(2-methylphenyl)-3-butenyl 1-[4,4-bis(2-methylphenyl)-3-butenyl]pyridinium-3-carboxylate bromide (18), respectively. The nonregioselective reaction of the pyridinium salts (17/18) with PhMgCl in THF at −23 °C using a catalytic amount of CuI afforded a mixture of isomeric 4-phenyl-1,4-dihydropyridyl (21 or 22) and 6-phenyl-1,6-dihydropyridyl (27 or 28) products in a ratio of approximately 1:1. All attempts to hydrolyze the 4,4-bis(2-methylphenyl)butyl or 3-butenyl ester moiety of 21/22 or 27/28 to a carboxyl group resulted in decomposition products. In contrast, the corresponding 3-(2-cyanoethyl) esters (23, 24, 29, 30) were readily converted to the corresponding carboxyl analogs (25, 26, 31, 32) via a β-elimination reaction of acrylonitrile using the non-nucleophilic base DBU. The 4-phenyl-1,4-dihydropyridyl (14, 25, 26) and 6-phenyl-1,6-dihydropyridyl (27/28 or 31/32) compounds inhibited the in vitro uptake of [3H]GABA into striatal prisms in the 21–44% range at a 10−4 M test compound concentration, relative to the reference drug nipecotic acid (87% inhibition). Structure–activity correlations showed the dihydropyridyl C-3 substituent was a determinant of [3H]GABA uptake where the potency order was CO2H > 2-(4,4-dimethyl-4,5-dihydrooxazolin-2-yl) > CO2(CH2)3CH-(o-tolyl)2 and CO2(CH2)2CH=C-(o-tolyl)2. Compounds possessing C-3 and (or) N-1 CO2(CH2)3CH-(o-tolyl)2 substituents were generally more potent than analogs having CO2(CH2)2CH=C-(o-tolyl)2 substituents. In general, 1,6-dihydropyridyl compounds were more potent than the corresponding 1,4-dihydropyridyl isomers. Keywords: 1,4- and 1,6-dihydropyridines, GABA-uptake inhibitors.
