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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?

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, M3 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 M3 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.

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Acknowledgements

This work was supported in part by RO1MH57635, KO2MH01366 and the NIMH Psychoactive Drug Screening Program to B.L.R. M.A.D. was supported in part by a supplement to RO1MH57635.

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Correspondence to Bryan L. Roth.

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Davies, M.A., Compton-Toth, B.A., Hufeisen, S.J. et al. 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?. Psychopharmacology 178, 451–460 (2005). https://doi.org/10.1007/s00213-004-2017-1

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Keywords

  • Clozapine
  • Atypical antipsychotic
  • N-desmethylclozapine
  • Muscarinic