Muscarinic cholinergic receptor binding: Influence of pimozide and chlorpromazine metabolites

Abstract

The relative muscarinic anticholinergic actions of phenothiazines and related drugs are thought to regulate the propensity of these agents to elicit extrapyramidal side effects, especially those resembling the symptoms of Parkinson's disease. Pimozide, which closely resembles the butyrophenones in its chemical structure and its potent and selective dopamine receptor blockade, differs from the butyrophenones in its relatively low incidence of extrapyramidal side effects. In assays of the binding of 3H-quinuclidinyl benzilate (QNB) to muscarinic sites, pimozide displays a high affinity for these cholinergic receptors, similar to drugs, such as thioridizine and clozapine, which also have a low incidence of extrapyramidal side effects. This observation supports the notion that muscarinic anticholinergic actions can ameliorate the propensity of a drug to elicit extrapyramidal effects. The structure-activity relationships of chlorpromazine metabolites in binding to muscarinic sites in the brain parallels some of their structure-activity relationships as neuroleptic agents. 7-Hydroxychlorpromazine, which has been proposed as an antischizophrenic drug, binds to the muscarinic receptor with a potency similar to that of chlorpromazine itself, suggesting that the incidence of extrapyramidal side effects of 7-hydroxychlorpromazine might be similar to those of chlorpromazine.