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 Myung A. Lee and Allan I. Levey and Uli Hacksell and Ethan S. Burstein and Robert e Davis and Mark R. Brann},  journal={Psychopharmacology},  year={2004},  volume={177},  pages={207-216},  url={https://api.semanticscholar.org/CorpusID:1024531}}
The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

243 Citations

Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo

Clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations, which may substantiate, at least in part, the atypical antipsychotic profile of clozAPine, as well as its central and peripheral side effects such as sedation and weight gain.

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.

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.

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.
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50 References

N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-d-aspartate receptor activity

Observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation.

Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists.

Current data suggest that xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects, and the preclinical data on the whole are promising for an antipsychotic-like profile.

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice.

Xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomelines has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD.

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