Calcium-channel drugs: structure-function relationships and selectivity of action

Calcium channels are ubiquitously distributed in excitable cells. The calcium-channel antagonists interact specifically at the L subclass of channels to mediate cardiovascular effects. These channels may be considered as pharmacologic receptors with specific drug binding sites and subject to a variety of regulatory influences. Each site is specific for agents of the three principal structural classes--the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines--and each exhibits defined structure-activity relationships. The 1,4-dihydropyridine structure exhibits both potent antagonistic and activator properties. The calcium channel antagonists exhibit considerable selectivity of action in the cardiovascular system, both between and within structural groups. This selectivity has a variety of causes including voltage dependence of the interaction, whereby the apparent affinity of the antagonist is determined by the membrane potential and stimulus pattern. Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1,4-dihydropyridines is reviewed.