[期刊论文][Full Papers]

出版年：1996

A group of racemic 3-[2-nitrooxyethyl（1,3-dinitrooxy-2-propyl or 4-nitrophenylethyl）] 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-[2-trifluoromethylphenyl （2-nitrophenyl or 3-nitrophenyl）]-3,5-pyridinedicarboxylates 13-15 were prepared using the Hantzsch reaction that involved the condensation of 2-nitrooxyethyl 9a , 1,3-dinitrooxy-2-propyl 9b or 4-nitrophenylethyl 9c acetoacetate with isopropyl 3-aminocrotonate 11 and 2-trifluoromethyl 12a , 2-nitro 12b or 3-nitro 12c benzaldehyde. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 13-15 exhibited superior, or equipotent, calcium channel antagonist activity （10^-8 to 10^-10 M range） relative to the reference drug nifedipine （IC₅₀ = 1.43 × 10^-8 M）. The R¹ C-3 ester substituent was a determinant of calcium channel antagonist activity where the potency order was CH₂CH₂ONO₂ > CH₂CH₂-C₆H₄-4-NO₂ CH（CH₂ONO₂）₂. In contrast, the C-4 R²-aryl substituent （2-CF₃-C₆H₄-, 2-O₂N-C₆H₄- or 3-O₂N-C₆H₄-） was not a major determinant of activity. Compounds 13a-15a , which possess a 3-（2-nitrooxyethyl） ester substituent exhibit superior calcium channel antagonist smooth muscle relaxant activity （IC₅₀ = 10^-10 M range） relative to nifedipine, could serve as potential probes to investigate the in vivo release of nitric oxide （NO） which induces vascular muscle relaxation.

Hantzsch 1,4-dihydropyridines;nitrooxy;calcium channels;smooth muscle relaxation