SYNTHESIS OF 4,4-BIS(2-METHYLPHENYL)-3-BUTENYL (AND BUTYL) ANALOGS OF4-PHENYL-1,4-DIHYDROPYRIDINE-3-CARBOXYLIC AND 6-PHENYL-1,6-DIHYDROPYRIDINE-3-CARBOXYLIC ACIDS AND THEIR EVALUATION AS NEURONAL GABA-UPTAKE INHIBITORS

Treatment of ihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (13) w ith NaH-DMSO, and then reaction with 1,1-bis(2-methylphenyl)-4-bromobu tane (12c) afforded ihydrooxazolin-2-yl)]-4-phenyl-1,4-dihydropyridine (14). Reaction of methyl nicotinate with 2.1 equivalents 12c or 1,1-b is(2-methylphenyl)-4-bromo-1-butene (11b) afforded 4,4-bis(2-methylphe nyl)butyl -bis(2-methylphenyl)butyl]pyridinium-3-carboxylate bromide ( 17) or 4,4-bis(2-methylphenyl)-3-butenyl 2-methylphenyl)-3-butenyl]pyr idinium-3-carboxylate bromide (18), respectively. The nonregioselectiv e reaction of the pyridinium salts (17/18) with PhMgCl in THF at -23 d egrees C using a catalytic amount of CuI afforded a mixture of isomeri c 4-phenyl-1,4-dihydropyridyl (21 or 22) and 6-phenyl-1,6-dihydropyrid yl (27 or 28) products in a ratio of approximately 1:1. All attempts t o 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 produ cts. In contrast, the corresponding 3-(2-cyanoethyl) esters (23, 24, 2 9, 30) were readily converted to the corresponding carboxyl analogs (2 5, 26, 31, 32) via a beta-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 inhib ited the in vitro uptake of [H-3]GABA into striatal prisms in the 21-4 4% range at a 10(-4) M test compound concentration, relative to the re ference drug nipecotic acid (87% inhibition). Structure-activity corre lations showed the dihydropyridyl C-3 substituent was a determinant of [H-3]GABA uptake where the potency order was CO2H > 2-(4,4-dimethyl-4 ,5-dihydrooxazolin-2-yl) > CO2(CH2)(3)CH-(o-tolyl)(2) and CO2(CH2)(2)C H=C-(o-tolyl)(2). Compounds possessing C-3 and (or) N-1 CO2(CH2)(3)CH- (o-tolyl)(2) substituents were generally more potent than analogs havi ng CO2(CH2)(2)CH=C-(o-tolyl)(2) substituents. In general, 1,6-dihydrop yridyl compounds were more potent than the corresponding 1,4-dihydropy ridyl isomers.