PHENOTHIAZINES ARE POTENT INHIBITORS OF OSTEOCLASTIC BONE-RESORPTION

1. We have previously shown that promethazine inhibits osteoclastic bo ne resorption in the in vitro bone slice assay (IC50=0.8 mu M), but th e mechanism(s) involved are unclear. 2. We have now tested the effects on osteoclast activity of five other structurally related compounds. Phenothiazine, chlorpromazine, amitriptyline, phenazine, and phenoxazi ne had IC50 values of 0.8, 0.9, 6, 7, and >10 mu M, respectively, in t he bone slice assay, indicating that the basic phenothiazine structura l element itself is important for osteoclast inhibitory activity. 3. T he results are discussed in terms of the known effects of phenothiazin es on plasma membrane fluidity, blocking of ion channels, and inhibiti on of calmodulin.