Current research is focused on ion channels medicating calcium translocation sodium influx, potassium efflux and nicotinic receptor-mediated sodium and calcium influx. Capacitative calcium influx, IP3-mediated release of intracellular calcium, and calcium ATPases are under study in leukemic HL-60 cells using a variety of agents including loperamide, trifluperazine, N-methyldihydropyridines, and imidazoles, such as SKF 9365, miconazole and clotrimazole, all of which affect capacitative calcium influx. Agents such as the steroidal maleimide U73122 that inhibits phospholipase A2, aminoethyl diphenyl borane and xestospongin that inhibit IP3-receptors are under study, as are the effects of caffeine, and analogs, which can activate influx of calcium, elicit release of calcium through ryanodine-sensitive channels, and inhibit IP3-dependent release of calcium. The mechanism, whereby loperamide selectivity enhances elevations of calcium maintained through capacitative calcium influx, remains undefined. A variety of lipophilic drugs, in addition to inhibition of calcium influx, can trigger calcium-release from endoplasmic reticulum through activation of phospholipase C. As yet, no selective inhibitor of capacitative calcium influx has been defined. A wide range of nicotinic agonists and noncompetitive blockers have been studied in cultured cells expressing central, ganglionic or neuromuscular nicotinic receptors in an attempt to define structural elements that will lead to selective nicotinic agents, certain of which might retain the analgetic properties of the frog skin alkaloid, epibatidine, while lacking the toxic effects of that alkaloid. Selective antagonists, non-competitive blockers and allosteric activators also are being sought. Effects of pumiliotoxins on activation and/or inhibition of sodium channels in neuroblastoma cells have been initiated in efforts to develop cardiotonic analogs with therapeutic potential for cardiac failure.
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