Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding

The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the parent drugs. The ring sulphoxides of levomepromazine, chlorpromazine and perphenazine, except dextro levomepromazine sulphoxide, were virtually inactive in all binding systems. The results indicate that the metabolites having the highest binding affinities for dopamine D2 receptor and alpha 1-adrenoceptor binding may contribute significantly to the therapeutic effect and side-effects of the drugs, and should be measured together with the parent drugs in blood level-effect studies.