Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.

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This comparison of the binding characteristics and pharmacology of 1,4-dihydropyridines indicates that the high-affinity binding sites studied in cardiac and smooth muscle cells represent a major site of action of these drugs, and that this site is the Ca2+ channel or a closely related protein. Electrophysiological studies suggest that the effects of both Ca2+ channel inhibitors and activators are voltage dependent. The apparent lack of agreement between the equilibrium dissociation constants for [3H]1 ,4-dihydropyridines and their potency in cardiac muscle may be due to conformational modifications that occur in the 1,4-dihydropyridine binding site as a result of voltage or other changes during membrane isolation. The selective effect of 1 ,4-dihydropyridines for vascular smooth muscle relative to cardiac muscle may be explained, in part, by differences in membrane potentials and Ca2+ channel regulatory mechanisms and, in part, by differences in receptor structure. 1,4-Dihydropyridine antagonists and activators appear to bind to a common site that is not the same as the binding site for nondihydropyridine Ca2+ channel antagonists.

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