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?

Rationale: Recent studies have suggested that the salutary actions of clozapine in schizophrenia may be due to selective activation of M₁ muscarinic receptors by clozapine and/or its major active metabolite N-desmethylclozapine. Objective: We systematically tested this hypothesis by screening a large number of psychoactive compounds, including many atypical antipsychotic drugs, for agonist activity at cloned, human M₁, M ₃ and M₅ muscarinic receptors. Results: Only three of the 14 atypical antipsychotic drugs we tested were found to possess partial agonist actions at M₁ muscarinic receptors (fluperlapine, JL13, clozapine). A few additional miscellaneous compounds had a modest degree of M₁ agonist actions. Only carbachol and N-desmethylclozapine had appreciable M ₃ muscarinic agonism at M₃ muscarinic receptors, although several were M₅ partial agonists including MK-212, N-desmethylclozapine and xanomeline. Conclusion: Although M₁ 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 M₁ muscarinic receptor activation. It is possible, however, that the M₁ agonism of N-desmethylclozapine contributes to the uniquely beneficial actions of clozapine. Thus, these results are consistent with the notion that a balanced degree of activity at multiple biogenic amine receptors, including M₁ muscarinic agonism, is responsible for the uniquely beneficial actions of clozapine.