Actions of phenothiazine analogues on dopamine-sensitive adenylate cyclase in neuronal and glial-enriched fractions from rat brain

Abstract

Dopamine (DA) at 10 −4M readily activated adenylate cyclase in homogenates of neuronal and glial-enriched fractions prepared from rat cerebral cortex, thalamus, striatum and the total homogenate from the striatum. Several derivatives of phenothiazines were tested for their ability to modify either the control component or the DA-sensitive receptor moiety of the enzyme. Dihydroxy analogues of chlorpromazine (CPZ), prochlorperazine, perphenazine. promazine and 7.8-dioxo-CPZ exhibited the most potent antagonism of either basal or DA-induced activation of the enzyme. In some cases at lowest concentrations the basal activity of adenylate cyclase was enhanced by these dihydroxy compounds. Parent compounds and corresponding monohydroxy metabolites of CPZ, prochlorperazine, perphenazine and fluphenazine were less potent toward antagonism of control enzyme preparations, but nevertheless exerted rather powerful antagonism at the DA-sensitive receptor site of adenylate cyclase. In this regard, 8-hydroxy derivatives were somewhat more potent than respective 7-hydroxy derivatives. Likewise, prochlorperazine and corresponding analogues were overall the most potent compounds. The 7-methoxy derivative of CPZ, along with thiothixene. thioridazine and haloperidol, was observed to exert a weaker antagonism of the DA-sensitive enzyme. Weakest inhibitory actions on either control or DA-sensitive sites of adenylate cyclase were seen with promazine, 2-OH- and 3-OH-promazine, clozapine, promethazine. CPZ-SO and 7,8-diMeO-CPZ. Phenothiazine, 3-OH-phenothiazine and 2-Cl-7,8-dioxo-phenothiazine were without effect. These findings suggest that molecular actions of pharmacologically active phenothiazines within the central nervous system are not totally reflected by the parent compounds, but may instead be additionally manifested by one or more metabolites.