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

  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},
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… 

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

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

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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.

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.



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5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.

Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries.

Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors.

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Effects of Desmethylclozapine on Fos Protein Expression in the Forebrain: In Vivo Biological Activity of the Clozapine Metabolite

Distribution of clozapine and desmethylclozapine between blood and brain in rats