Interactions of neuroleptic metabolites with dopaminergic, alpha adrenergic and muscarinic cholinergic receptors.

Using the radioligand binding assay, the in vitro potency of three neuroleptic drugs at dopaminergic ([3H]spiroperidol), alpha adrenergic ([3H]WB-4101) and muscarinic cholinergic ([3H]quinuclidinyl benzilate) receptor binding sites was compared to the potency of 12 metabolites of these drugs at the same receptors. Metabolites resulting from the oxidation of the ring sulfur of either thioridazine or fluphenazine were very weak at all three receptors. On the other hand, two metabolites, thioridazine-S-sulfoxide (mesoridazine) and thioridazine-S-sulfone (sulforidazine) were more potent than thioridazine at both the dopaminergic and alpha adrenergic receptors but less potent at muscarinic receptors. The binding data correlated very well with published clinical data on the relative potency and incidence of autonomic and extrapyramidal side effects of these three drugs. Since several of the metabolites which are potent receptor blockers accumulate in the plasma during chronic neuroleptic treatment, it appears that both the therapeutic and side effects of neuroleptic drug treatment are due in large part to metabolites of the administered drug.