Interactions of neuroleptic metabolites with dopaminergic, alpha adrenergic and muscarinic cholinergic receptors
Bylund, D.B.
Journal of Pharmacology and Experimental Therapeutics 217(1): 81-86
1981
ISSN/ISBN: 0022-3565 PMID: 6110776 Document Number: 168921
Using the radioligand binding assay, the in vitro potency of 3 neuroleptic drugs [thioridazine, chlorpromazine and fluphenazine] at dopaminergic ([3H]spiroperidol), .alpha.-adrenergic ([3H]WB-4101) [2-[N-(2,6-dimethoxyphenoxyethyl)] aminomethyl-1,4-benzodioxan] and muscarinic cholinergic ([3H]quinuclidinyl benzilate) receptor binding sites was compared to the potency of 12 metabolites of these drugs [thioridazine-S-sulfoxide, thioridazine-S-sulfone, northioridazine-S-sulfoxide, thioridazine-R-sulfoxide, thioridazine-disulfone, thioridazine-disulfoxide, 7-hydroxychlorpromazine, methoxychlorpromazine, fluphenazine-R-sulfoxide, 7-hydroxyfluphenazine and deshydroxyethylfluphenazine] at the same receptors [3]. Metabolites resulting from the oxidation of the ring sulfur of either thioridazine or fluphenazine were very weak at all 3 receptors. 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 3 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.