Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-(unsubstituted, 2-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl)-1,4-dihydropyridine

Abstract

The molecular structures of 2,6-dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine and the 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl derivatives were determined by X-ray diffraction methods. The dihydropyridine ring in each of the compounds exists in a boat-type conformation. However, the degree of ring puckering varies among the compounds. The observed ring distortions were found to be influenced to a great extent by the position of the substituent in the 4-phenyl ring and the conformation about the interring bond. The distortion at the apical nitrogen of the dihydropyridine ring was found to be linearly related to that at the apical tetrahedral carbon. A correlation was observed between the pharmacological activities of this class of calcium channel antagonists, determined by their ability to inhibit the Ca2+-dependent muscarinic mechanical responses of guinea pig ileal longitudinal smooth muscle, and the magnitude of the 1,4-dihydropyridine ring puckering; the more active compounds exhibited the smallest degree of ring distortion from planarity.