SYNTHESIS AND SMOOTH-MUSCLE CALCIUM-CHANNEL ANTAGONIST EFFECTS OF DIALKYL DIHYDRO-2,6-DIMETHYL-4-ARYL-3,5-PYRIDINEDICARBOXYL CONTAINING A NITROOXY OR NITROPHENYL MOIETY IN THE 3-ALKYL ESTER SUBSTITUENT

A group of racemic 3-[2-nitrooxyethyl (1,3-dinitrooxy-2-propyl or 4-ni trophenylehtyl)] 5-osopropyl 14-dihydro-2,6-dimethyl-4-[2-trifluoromet hylphenyl (2-nitrophenyl or 3-nitrophenyl)]-3,5-pyrodinedicarboxylates 13-15 were prepared using the Hantzsch reaction that involved the con densation of 2-nitrooxyethyl 9a, 1,3-dinitrooxy-2-propyl 9b or 4-nitro phenylethyl 9c acetoacetate with isopropyl 3-aminocrotonate 11 and 2-t rifluoromethyl 12a, 2-nitro 12b or 3-nitro 12c benzaldehyde. In vitro calcium channel antagonist activities were determined using a guinea p ig ileum longitudinal smooth muscle assay. Compounds 13-15 exhibited s uperior, or equipotent, calcium channel antagonist activity (10(-8) to 10(-10) M range) relative to the reference drug nifiedipine (IC50=1.4 3 x 10(-8) M). The R(1) C-3 ester substituent was a determined of calc ium channel antagonist activity where the potency order was CH2CH2ONO2 > CH2CH2-C6H4-4-NO2 greater than or equal to CH(CH2ONO2)(2). In contr ast, the C-4 R(2)-aryl substituent (2-CF3-C6H4-, 2-O2N-C6H4- or 3-O2N- C6H4-) was not a major determinant of activity. Compounds 13a-15a, whi ch possess a 3-(2-nitrooxyethyl) ester substituent exhibit superior ca lcium channel antagonist smooth muscle relaxant activity (IC50=10(-10) M range) relative to nifedipine, could serve as potential probes to i nvestigate the in vivo release of nitric oxide (NO) which induces vasc ular muscle relaxation.