Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors.

  title={Clozapine interaction with the M2 and M4 subtypes of muscarinic receptors.},
  author={Pavel Michal and Michaela Lys{\'i}kov{\'a} and Esam E. El‐Fakahany and Stanislav Tuček},
  journal={European journal of pharmacology},
  volume={376 1-2},

Allosteric interactions at the M3 muscarinic acetylcholine receptor

The dramatic changes in cooperativities and affinities of allosteric ligands at K523E did not result in generation of the M1 phenotype, and the large changes in K523Q result from the introduction of the negatively charged glutamate residue and not the loss of the positively charged lysine.

The Muscarinic Acetylcholine Receptor Agonist BuTAC Mediates Antipsychotic-Like Effects via the M4 Subtype

A role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC is supported and implicate M4 aChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with schizophrenia.

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

It is demonstrated for the first time that NDMC acts as a selective and efficacious δ-opioid receptor agonist and suggested that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine.

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Preliminary data indicate that reduction of mus carinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptors availability.

Comparison of the in-vivo muscarinic cholinergic receptor availability in patients treated with clozapine and olanzapine.

  • T. Raedler
  • Psychology, Medicine
    The international journal of neuropsychopharmacology
  • 2007
The results suggest that treatment with clozapine results in a stronger blockade of the muscarinic cholinergic receptors than with olanzapine, compatible with the higher rates of anticholinergic side-effects seen with clazapine in clinical practice.

Muscarinic mechanisms of antipsychotic atypicality

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.

Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice

It is suggested that disruption of the M5 receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs.

Dual effects of muscarinic M2 acetylcholine receptors on the synthesis of cyclic AMP in CHO cells: dependence on time, receptor density and receptor agonists

It is proposed that the Gs‐mediated stimulatory component of the effect of muscarinic M2 receptors on cyclic AMP synthesis only occurs if the density of activated receptors is high enough to saturate the Gi proteins and proportionate to the receptors' low affinity for theGs proteins.

1.2 Cholinergic Mechanisms in Schizophrenia

Substantial evidence exists for the involvement of both muscarinic and nicotinic cholinergic neurotransmission in the pathophysiology of schizophrenia, particularly the a7-nicotinic receptor, which requires high levels of nicotine for activation.



Interactions of agonists with M2 and M4 muscarinic receptor subtypes mediating cyclic AMP inhibition.

The rat striatal and N1E-115 M4 receptor differed in their binding of oxotremorine and pilocarpine, indicating that these two M4 systems were not pharmacologically identical.

Subtype selectivity of the positive allosteric action of alcuronium at cloned M1-M5 muscarinic acetylcholine receptors.

Differences between the effects of alcuronium on individual muscarinic receptor subtypes are apparently responsible for differences between the allosteric effects ofAlcur onium on mus carinic receptors in various tissues that had been described previously.

Clozapine is a potent and selective muscarinic M4 receptor agonist.

Effects of clozapine on rat striatal muscarinic receptors coupled to inhibition of adenylyl cyclase activity and on the human cloned m4 receptor

Results show that at the striatal M4 receptors clozapine is a potent and competitive antagonist, whereas at the cloned m4 receptor it elicits both agonist and antagonist effects.

Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells.

Clozapine's unusual efficacy in refractory schizophrenic patients and its low incidence of extrapyramidal side effects may be explained, but because most other atypical neuroleptics studied lacked high affinity and selectivity at muscarinic receptor subtypes, it is likely that other mechanisms are involved as well.

Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells.

The diverse binding profiles of individual cloned receptors and the widespread distribution of m1-m4 mRNAs indicate that radioligand binding studies performed on primary tissues may actually be assessing the composite properties of a heterogeneous mixture of muscarinic receptor subtypes.

Allosteric modulation of muscarinic acetylcholine receptors.