Inhibition of the catalytic site of adenylate cyclase in the central nervous system by phenothiazine derivatives

Abstract

Inhibition by phenothiazine derivatives was evaluated with respect to the catalytic component of adenylate cyclase prepared from either a high speed particulate fraction of rat cerebral cortex and hypothalamus or neuronal and glial-enriched fractions from rat and rabbit cerebral cortex. The dihydroxylated analogues of chlorpromazine, prochlorperazine, perphenazine and promazine along with the dioxo form of chlorpromazine were the most potent inhibitors of either basal activity or fluoride activation of the enzyme. To a lesser extent inhibition of adenylate cyclase was observed with the parent compounds (including fluphenazine and promethazine) and their respective monohydroxylated or methoxylated analogues. The enzyme from the high speed particulate fraction was more resistant to inhibition by these compounds than the neuronal and glial enzymes. Compounds which were without effect on adenylate cyclase were: chlorpromazine sulphoxide, haloperidol, phenothiazine, 3-hydroxyphenothiazine and 2-chloro-7,8-dioxophenothiazine. A preliminary investigation revealed that 7,8-dihydroxychlorpromazine and 7,8-dioxochlorpromazine exerted profound antagonism of norepinephrine sensitive adenylate cyclase in neuronal and glialenriched fractions. In this regard chlorpromazine and 7-hydroxychlorpromazine displayed an intermediate potency while 8-hydroxychlorpromazine was a weak antagonist of the enzyme. Chlorpromazine sulphoxide and 7,8-dimethoxychlorpromazine were without an effect. The data suggest that the actions of specific metabolites of phenothiazines may account for additional intracellular effects following experimental or therapeutic administration of any parent compourd.