Active conformation of 1,4-dihydropyridine calcium entry blockers. Effect of size of 2-aryl substituent on rotameric equilibria and receptor binding.
The conformational requisites at the receptor for unsymmetrically substituted phenyl-1,4-dihydropyridine calcium entry blockers are examined by screening a series of (2'-halophenyl)-1,4-dihydropyridines 1-4, with increasing bulk at the 2'-position of the phenyl ring, for their ability to relax potassium-contracted rabbit aortic smooth muscle and to competitively displace [3H]nitrendipine from its specific binding sites on guinea pig skeletal muscle. The fraction of synperiplanar rotamer in solution for these compounds, as determined by the nuclear Overhauser enhancement method, shows a positive correlation with vasorelaxant activity and receptor binding affinity. These findings are consistent with the synperiplanar rotamer of nonrigid unsymmetrically substituted phenyl 1,4-dihydropyridine calcium channel blockers being the receptor-bound conformation.
Rovnyak
G
G
Department of Chemistry/Cardiopulmonary, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Andersen
N
N
Gougoutas
J
J
Hedberg
A
A
Kimball
S D
SD
Malley
M
M
Moreland
S
S
Porubcan
M
M
Pudzianowski
A
A
D000818:Animals; D001011:Aorta / Q000502:physiology; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006219:Halogens; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D006219:Halogens; D011978:Receptors, Nicotinic; D009568:Nitrendipine