Calcium antagonists. History and perspective.

The calcium channel antagonists are a heterogeneous group of drugs acting on one class of voltage-dependent channel. Their modes and sites of actions are reviewed in this historical perspective and placed in the context of the cellular events underlying homeostasis. Calcium channel antagonists should be regarded as a subset of a larger family of Ca2+ modulators, agents that block or activate functions at a variety of control loci for Ca2+ homeostasis. In a number of important respects, the Ca2+ channel may be viewed as a pharmacologic receptor that defines the existence of specific drug binding sites and their regulation by homologous and heterologous influences. We describe the factors that define the selectivity of action of channel antagonists, with particular emphasis on state-dependent interactions controlled by voltage-modulated drug interactions, and discuss future developments in Ca2+ channel ligands, emphasizing the contributions of molecular biology and the development of more specific and selective agents.