Inhibition of D-Amino acid oxidase by phenothiazines
Harris, Sheldon R.
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Although the pharmacology and chemical effects of the phenothiazine derivatives have been extensively studied, very little is known concerning the biochemical mechanisms by which they exert their pharmacological effects. Underlying most of the work in this field is the belief that these compounds have certain enzymes as their primary targets or receptor sites. Thus chlorpromazine (CP Z) has been found to inhibit a wide variety of enzymes including cytochrome oxidase, glucose-phosphate dehydrogenase, hexokinase, and ATPase and to uncouple oxidative phosphorylation. However, excessive concentrations of CPZ were required to inhibit these systems and in most cases there was no good correlation between the antipsychotic behavior of these derivatives and their inhibitory capacity. Although the differences in inhibitory potency can not be explained yet in terms of binding sites, the approximate correlation between Ki and the usual daily dosage of these compounds in antipsychotic therapy, the failure of phenothiazines with little (if any) tranquilization properties to inhibit D-AAO, and the fact that the concentrations of drug required for inhibition (Ki) were well within the range which may be encountered in vivo all make more tenable the hypothesis that the phenothiazine tranquilizers might exert their effects by inhibiting flavo enzymes. [TRUNCATED]
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