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

Imidazoles, such as SKF 96365, clotrimazole, and miconazole, have represented the major class of inhibitors of store-operated calcium (SOC) channels. In HL60 cells, ATP and thapsigargin cause depletion of intracellular calcium stores, resulting in activation of SOC channels. Tricyclic phenothiazines and other tricyclics, such as amitriptyline and clozapine, were found to inhibit 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 inhibiting SOC channels, imidazoles, in particular, miconazole, caused a marked release of intracellular calcium, apparently from the same intracellular pool depleted by ATP and thapsigargin. The phenothiazines and the other two tricyclics caused little or no release of intracellular calcium compared to that caused by miconazole. However, these compounds did cause a significant decrease in the release of intracellular calcium elicited by subsequent 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, the tricyclics. The augmentation of calcium levels by loperamide indicated that these agents had, through release of intracellular calcium, caused activation of SOC channels. Published 1999 Wiley-Liss, Inc.