New developments in Ca2+ channel antagonists.

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.