SYNTHESIS, BIOLOGICAL EVALUATION, CALCIUM-CHANNEL ANTAGONIST ACTIVITY, AND ANTICONVULSANT ACTIVITY OF FELODIPINE COUPLED TO A DIHYDROPYRIDINE-PYRIDINIUM SALT REDOX CHEMICAL DELIVERY SYSTEM

3-(2-Hydroxyethyl) 5-methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-py ridinedi carboxylate (7) was prepared using a modified Hantzsch reacti on, which was then elaborated to 1-methyl-1,4-dihydropyrid-3-yl)carbon yl]oxy]ethyl] 5-methyl l-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxyl ate [10, felodipine-chemical delivery system (CDS)]. The equipotent 3- (2-hydroxyethyl) 7 (IC50 = 3.04 x 10(-8) M) and felodipine-CDS (10, IC 50 = 3.10 x 10(-8) M) were, respectively, 2- and 21-fold less potent c alcium channel antagonists than the reference drugs nimodipine (IC50 = 1.49 x 10(-8) M) and felodipine (IC50 = 1.45 x 10(-9) M). Compounds 7 , 10, nimodipine, and felodipine are highly lipophilic (K-p = 236, 366 , 187, and 442, respectively). 3-(2-Hydroxyethyl) 7, felodipine-CDS (1 0), and felodipine provided protection against maximal electroshock-in duced seizures in mice but were inactive in the subcutaneous metrazol anticonvulsant screen. In vitro incubation studies of felodipine with rat plasma and 20% brain homogenates showed felodipine was very stable in both biological media. Similar incubations of felodipine-CDS showe d its rate of biotransformation followed psuedo-first-order kinetics w ith half-lives of 15.5 h in rat plasma and 1.3 h in 20% rat brain homg enates. In vivo biodistribution of felodipine and felodipine-CDS was s tudied. Uptake of felodipine in brain produced a peak brain concentrat ion of 5 mu g/g of brain tissue at 5 min, after which it rapidly egres sed from brain resulting in undetectable levels at 60 min. Peak blood concentrations of 10 occurred at about 7 min followed by a rapid decli ne to a near undetectable concentration by 17 min. The pyridinium salt species 9, resulting from oxidation of 10, also reached peak concentr ations at about 7 min but it slowly decreased to undetectable concentr ations at 2 h. 3-(2-Hydroxyethyl) 7 remained at near undetectable conc entrations throughout a 2 h time period. Localization of 10 in brain p rovided a peak concentration of 4.2 mu g/g of brain tissue at 5 min an d then decreased to negligible concentrations at 15 min. The concentra tion of oxidized pyridinium species 9 in brain remained high providing detectable concentrations up to 4 days. In contrast, the concentratio n of the 3-(2-hydroxyethyl) hydrolysis product 7 in brain remained at very low levels throughout the study. The slow hydrolysis rate of the pyridinium ester 9 to the 3-(2-hydroxyethyl) 7 and the rapid egression of felodipine-CDS from brain are believed to contribute to the modera te anticonvulsant activity exhibited hy the felodipine-CDS (10).