A COMPARATIVE STUDY OF DIHYDROXYLATED PHENOTHIAZINE DERIVATIVES AS MITOCHONDRIAL INHIBITORS

— —The effects of several dihydroxylated phenothiazine derivatives on brain mitochondrial calcium retention, respiration and ATP synthesis were studied and compared to those of 7,8‐dihydroxy‐chlorpromazine. This compound has previously been shown to disrupt retention of calcium accumulated in the presence of ATP, to inhibit state III and state IV respiration with glutamate as substrate and to inhibit ATP synthesis. It was found that 2,3‐dihydroxypromazine has little effect on mitochondrial calcium retention, but is a potent inhibitor of oxidative phosphorylation. 3,7‐Dihydroxychlorpromazine and 3,8‐dihydroxychlorpromazine produced a relatively slow and incomplete efflux of pre‐accumulated calcium and caused a limited inhibition of respiration. 7,8‐Dihydroxyperphenazine and 7,8‐dihydroxyprochlorperazine promoted an efflux of mitochondrial calcium and inhibited mitochondrial respiration as was seen with 7,8‐dihydroxychlorpromazine. The effects seen with 7,8‐dioxochlorpromazine are also similar to those seen with 7,8‐dihydroxychlorpromazine, suggesting that oxidation products may contribute to the inhibitory effects observed.