Phenothiazines are potent inhibitors of osteoclastic bone resorption.

1. We have previously shown that promethazine inhibits osteoclastic bone resorption in the in vitro bone slice assay (IC50 = 0.8 microM), but the 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 phenoxazine had IC50 values of 0.8, 0.9, 6, 7, and > 10 microM, respectively, in the bone slice assay, indicating that the basic phenothiazine structural element itself is important for osteoclast inhibitory activity. 3. The results are discussed in terms of the known effects of phenothiazines on plasma membrane fluidity, blocking of ion channels, and inhibition of calmodulin.