Crystal Structures and Pharmacologic Activities of 1,4-Dihydropyridine Calcium Channel Antagonists of the Isobutyl Methyl 2,6-Dimethyl-4-(substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (Nisoldipine) Series

A series of isobutyl methyl 2,6-dimethyl-4-(X-substituted phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (X = H, 2-NO₂, 3-NO₂, 3-CN, 3-MeO, 4-F, 2-CF₃, 3-CF₃, and 4-C1) related to and including nisoldipine (X = 2-NO₂) has been synthesized, their solid-state structures determined by X-ray analysis (X = H, 2-NO₂, 3-NO₂, 3-CN, 3-MeO, and 4-F), and their pharmacologic activities determined, as the racemic compounds, against [³H]nitrendipine binding and K⁺-depolarization-induced tension responses in intestinal smooth muscle as measures of Ca²⁺ channel antagonist activity. Comparisons of structure are presented to previously analyzed 1,4-dihydropyridines. The degree of 1,4-dihydropyridine ring puckering is dependent on the nature and position of the phenyl ring substituent and the adopted interring conformation. Different ester substituents affect 1,4-dihydropyridine ring puckering to a small extent in most cases. Pharmacologic and radioligand binding activities for the nine compounds studied show a parallel dependence on phenyl ring substituent, but the compounds are approximately 10-fold more active in the radioligand binding assay than in the pharmacologic assay. Consistent with a previous report for the nifedipine series (Fossheim et al. J. Med. Chem. 1982,25,126), pharmacologic activity increases with increasing 1,4-dihydropyridine ring planarity.