The Ca2+ channel drugs, including the clinically available verapamil, nifedipine and diltiazem, enjoy prominent use both as therapeutic agents in the control of number of cardiovascular disorders, but also as molecular probes with which to analyze the structure and function of voltage- dependent Ca2+ channels. Much remains to be established concerning the underlying sites and mechanisms of action of these agents, both antagonists and activators. Synthetic chemical, radioligand binding and pharmacologic approaches will be used to obtain a number of related objectives with particular references to 1,4-dihydropyridines. a. A systematic exploration of the structure-activity relationship of the 1,4-dihydropyridine binding site to map out the geometries and energetics of the binding surface. Radioligand binding, tissue pharmacology and 45Ca2+ uptake studies will characterize biological effects of both activators and antagonists. b. Synthesis of irreversible probes - to characterize relationship between channel number and response and to define location of 1,4-DHP binding sites. c. Synthesis of probes to aid in the physical localization of drug molecules d. Measurement of turnover rates of Ca2+ channels and associated probes e. Analysis of homologous and heterologous regulation of Ca2+ channel function by drugs and hormones f. Identification of the role of membrane potential and G protein activation on the affinities of drugs and receptor sites I anticipate that these approaches will be of use to determine the molecular basis of selectivity of action of Ca2+ channel ligands in physiological and pathological states.