Reactions of chloropromazine cation radical with physiologically occurring nucleophiles

The reactions between chlorpromazine cation radical and a variety of physiologically occurring nucleophiles, which involve formation of a covalent, yet reversible bond, have been examined. As reported earlier, this reaction does not involve disproportionation of the radical but, rather, direct reaction between radical and nucleophile. The resulting adduct further reacts to form chlorpromazine sulfoxide or hydroxylated derivatives, and the original nucleophile is regenerated. The products and kinetics of the reaction depend strongly on the identity of the nucleophile, with the sulfhydryl group being the fastest and water being the slowest of the nucleophiles studied. The likely involvement of these reactions in the metabolism of chlorpromazine is discussed. In addition, it is proposed that the radical/nucleophile interaction is a reasonable model reaction for the effects of chlorpromazine radical on neuronal enzymes and receptor sites.