Inhibitors of store-operated calcium channels: Imidazoles, phenothiazines,and other tricyclics

Imidazoles, such as SKF 96365, clotrimazole, and miconazole, have represent ed the major class of inhibitors of store-operated calcium (SOC) channels. In HL60 cells, ATP and thapsigargin cause depletion of intracellular calciu m stores, resulting in activation of SOC channels. Tricyclic phenothiazines and other tricyclics, such as amitriptyline and clozapine, were found to i nhibit SOC channels of HL60 cells, with trifluoperazine being of comparable potency to the imidazoles. The effects of the imidazoles and tricyclics on intracellular calcium levels in HL60 cells were compared. In addition to i nhibiting SOC channels, imidazoles, in particular, miconazole, caused a mar ked release of intracellular calcium, apparently from the same intracellula r pool depleted by ATP and thapsigargin. The phenothiazines and the other t wo tricyclics caused little or no release of intracellular calcium compared to that caused by miconazole. However, these compounds did cause a signifi cant decrease in the release of intracellular calcium elicited by subsequen t addition of ATP or thapsigargin. Loperamide, which appears to selectively and positively modulate activated SOC channels, augments the elevation of intracellular calcium elicited by the imidazoles and, to a lesser extent, t he tricyclics. The augmentation of calcium levels by loperamide indicated t hat these agents had, through release of intracellular calcium, caused acti vation of SOC channels. Published 1999 Wiley-Liss, Inc.