It is proposed to use electrochemistry, rapid-scanning spectrophotometry, and liquid chromatography to examine the oxidation of chlorpromazine and related phenothiazines in aqueous solution. The structures and reactions of materials formed upon chemical or electrochemical oxidation of chlorpromazine, fluphenazine, and the hydroxylated chlorpromazines will be investigated, with particular attention to the importance of the findings to the pharmacology of the parent compounds. Specifically, the reactions of chlorpromazine cation radical with physiological nucleophiles and nucleophilic peptides will be studied, with regard to the relationship between these reactions and theories of drug/receptor interactions. Reactions of other phenothiazine radicals, particularly fluphenazine, will be compared to those of chlorpromazine. Finally, the initial work on oxidation reactions of hydroxylated chlorpromazine metabolites will be continued. It is anticipated that the chemical knowledge resulting from the proposed work will aid the evaluation of theories on the mechansim of action of phenothiazine drugs. In addition, chemical information may provide new insight into the involvement of cation radicals and other metabolites in the anti-psychotic activity of the phenothiazines.
NIH ExPorter
NIH ExPorter