SYNTHESES, CALCIUM-CHANNEL ANTAGONIST AND ANTICONVULSANT ACTIVITIES OF SUBSTITUTED 1,4-DIHYDRO-3,5-PYRIDINEDICARBOXYLATES CONTAINING VARIOUS 3-ALKYL ESTER SUBSTITUENTS

A group of 3-alkyl 5-isopropyl ,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylates 10-20 containing an amine, quaternary ammonium, aryl(heter oaryl)alkenyl, 4-(4-fluorophenyl)piperazin-1-yl or methoxy moiety in t he C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl-2, 3-NO2, 3-NMe(2), 4-NMe(2) or 3,4,5-(OMe)3 X-subst ituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined usin g a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-ni trophenyl series of compounds, the C-3 ester R-substituent was a deter minant of CCA activity where the relative potency order was -CH2CH2CH= C-(2-methyIphenyl)(2) greater than or equal to-CH(2)CH(2)NMe(2).HCl > -CH2CH2CH=C-(3-methyl-2-thienyl)(2) > -CH(2)CH(2)(+)NMe(3) I-. The pos ition and nature of the C-4 phenyl X-substituent, were also determinan ts of CCA activity where the relative activity order was 3-NMe(2) > 4- NMe(2) > 3,4,5-(OMe)(3). Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting againist scMet induced seizures, except for 10 {X = 2, 3-Cl-2, R = 2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl} and 14a (X = 3- NMe(2).HCl, R = CH(2)CH(2)OMe), which exhibited modest activity. Compo und 11a (X = 3-NO2, R = -CH(2)CH(2)NMe(2).HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH(2)CH(2)(+)NMe(3) I-, Kp = 0.15), are lipophil ic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coeffi cients (Kp) in the 121-424 range relative to the reference drug nimodi pine (Kp = 187). The structure-activity relationships acquired reinfor ce the concept that calcium is only one of several factors that are in volved in seizure generation.