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 = 0.68 pi + 2.50 sigma m -0.47Lmeta -3.40B1para + 11.31, which had a correlation coefficient of 0.89. The full data set was best correlated by eq 11, log 1/C = 0.62 pi + 1.96 sigma m -0.44Lmeta -3.26B1para -1.51Lmeta' + 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.
Coburn
R A
RA
Department of Medicinal Chemistry, School of Pharmacy, State University of New York, Buffalo 14260.
Wierzba
M
M
Suto
M J
MJ
Solo
A J
AJ
Triggle
A M
AM
Triggle
D J
DJ
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008433:Mathematics; D009119:Muscle Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship
D015220:Calcium Channels; D004095:Dihydropyridines; C038806:1,4-dihydropyridine