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. Davies, Beth Ann Compton-Toth, Sandra J. Hufeisen, Herbert Y. Meltzer, Bryan L. Roth*

*Corresponding author for this work

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)451-460
Number of pages10
JournalPsychopharmacology
Volume178
Issue number4
DOIs
StatePublished - Apr 1 2005

Keywords

  • Atypical antipsychotic
  • Clozapine
  • Muscarinic
  • N-desmethylclozapine

ASJC Scopus subject areas

  • Pharmacology

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