1,4-Dihydropyridine Antagonist Activities at the Calcium Channel: A Quantitative Structure-Activity Relationship Approach

The effect of 46 1,4-dihydropyridine-type calcium channel antagonists on the tonic contractile response of longitudinal muscle strips of guinea pig ileum was determined. 2,6-Dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine (13) and 13 ortho-, 15 meta-, and seven para-monosubstituted and 10 polysubstituted aromatic derivatives of 13 were studied. The pharmacological activities of the monosubstituted derivatives were best correlated by eq 10, log 1/C = 0.68π + 2.50σ_m - 0.47L_meta - 3.40Bl_para + 11.31, which had a correlation coefficient of 0.89. The full data set was best correlated by eq 11, log 1/C = 0.62π + 1.96σ_m - 0.44L_meta - 3.26Bl_para - 1.51L_meta′- + 14.23, which had a correlation coefficient of 0.90. Equations of similar form but involving an ortho steric term were found to correlate the radioligand binding data for this class of compounds.