Mar 15, 2005

The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions?

Marilyn A DaviesBryan L Roth


Recent studies have suggested that the salutary actions of clozapine in schizophrenia may be due to selective activation of M(1) muscarinic receptors by clozapine and/or its major active metabolite N-desmethylclozapine. We systematically tested this hypothesis by screening a large number of psychoactive compounds, including many atypical antipsychotic drugs, for agonist activity at cloned, human M(1), M(3) and M(5) muscarinic receptors. Only three of the 14 atypical antipsychotic drugs we tested were found to possess partial agonist actions at M(1) muscarinic receptors (fluperlapine, JL13, clozapine). A few additional miscellaneous compounds had a modest degree of M(1) agonist actions. Only carbachol and N-desmethylclozapine had appreciable M(3) muscarinic agonism at M(3) muscarinic receptors, although several were M(5) partial agonists including MK-212, N-desmethylclozapine and xanomeline. Although M(1) muscarinic receptor-selective partial agonists have shown promise in some preclinical antipsychotic drug models, these studies indicate that it is unlikely that the salutary actions of clozapine and similar atypical antipsychotic drugs are mediated solely by M(1) muscarinic receptor activation. It is possible, however, that the...Continue Reading

Mentioned in this Paper

Antipsychotic Effect
Atypical Antipsychotic [EPC]
Chinese Hamster Ovary Cell
Xanomeline tartrate
JL 13

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here