The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine

@article{Weiner2004TheRO,
  title={The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine},
  author={David M Weiner and Herbert Y. Meltzer and Isaac Veinbergs and E Donohue and Tracy A. Spalding and T. T. Smith and Nina Mohell and Scott C. Harvey and Jelveh Lameh and Norman R. Nash and Kimberly E. Vanover and Roger Olsson and Karu Jayathilake and M. A. Lee and Allan I. Levey and Uli Hacksell and Ethan S. Burstein and R. E. Davis and Mark R. Brann},
  journal={Psychopharmacology},
  year={2004},
  volume={177},
  pages={207-216}
}
RationaleClozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described.Objectives and methodsTo comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine… 
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209 Citations
Highly Influential Citations
16
Background Citations
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Methods Citations
4
Results Citations
16

209 Citations

Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse

Administration of NMDC reversed a striking hyperactive phenotype in the phospholipase C-&bgr;1 knockout mouse, whereas no significant effects were observed in wild-type animals, highlighting the potential role of muscarinic activity in the behavioural response to NDMC.

Electrophysiological evidence showing muscarinic agonist–antagonist activities of N-desmethylclozapine using hippocampal excitatory and inhibitory neurons

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

NDMC, because of its M1 agonism, may more effectively treat the cognitive impairments observed in schizophrenia than clozapine itself; and M1 receptor agonism may be a valuable target for the development of drugs that can improve cognitive deficit in schizophrenia, and perhaps other neuropsychiatric disorders as well.

Discriminative stimulus properties of N-desmethylclozapine, the major active metabolite of the atypical antipsychotic clozapine, in C57BL/6 mice

Clozapine and its major metabolite NDMC share in-vivo behavioral properties that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs, and probably reflect a compound cue similar to that of its parent drug clozAPine due to its diverse binding profile.

The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats

Findings suggest that NDMC produces discriminative stimulus effects that are different from those elicited by its parent drug CLZ, which may be due to the agonist properties of NDMC at M1 muscarinic cholinergic receptors.

The clozapine metabolite N-desmethylclozapine displays variable activity in diverse functional assays at human dopamine D₂ and serotonin 5-HT₁A receptors.

N-Desmethylclozapine: Is There Evidence for its Antipsychotic Potential?

NDMC's biological activity is examined in the context of the pathophysiology of schizophrenia and the few recent preclinical and clinical studies of NDMC's potential antipsychotic effects are critically evaluated to predict its therapeutic potential.

Behavioral effects of N-desmethylclozapine on locomotor activity and sensorimotor gating function in mice—Possible involvement of muscarinic receptors

Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia

The finding that the relationship between clozapine/N-desmethylclozAPine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinerential mechanism underlying this relationship.

Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats--possible involvement of activation of M(1) muscarinic receptors.

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