Mixed Agonist–Antagonist Properties of Clozapine at Different Human Cloned Muscarinic Receptor Subtypes Expressed in Chinese Hamster Ovary Cells

Olianas, Maria C.; Maullu, Carlo; Onali, Pierluigi

doi:10.1016/s0893-133x(98)00048-7

Cited by 63 publications

(35 citation statements)

References 29 publications

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“…An important feature of clozapine is its ability to bind with high affinity to acetylcholine (ACh) muscarinic receptors and to act as a mixed agonist/antagonist (Zorn et al, 1994;Zeng et al, 1997;Olianas et al, 1997Olianas et al, , 1999Michal et al, 1999). A similar property has recently been demonstrated for NDMC.…”

Section: Introductionmentioning

confidence: 90%

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

Onali

Olianas

2006

Neuropsychopharmacol

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The present study examined the effects of N-desmethylclozapine (NDMC), a biologically active metabolite of the atypical antipsychotic clozapine, at cloned human opioid receptors stably expressed in Chinese hamster ovary (CHO) cells and at native opioid receptors present in NG108-15 cells and rat brain. In CHO cells expressing the d-opioid receptor (CHO/DOR), NDMC behaved as a full agonist both in stimulating [ 35 S]GTPgS binding (pEC 50 ¼ 7.24) and in inhibiting cyclic AMP formation (pEC 50 ¼ 6.40). NDMC inhibited [ 3 H]naltrindole binding to CHO/DOR membranes with competition curves that were modulated by guanine nucleotides in an agonistlike manner. Determination of intrinsic efficacies by taking into consideration both the maximal [ 35 S]GTPgS binding stimulation and the extent of receptor occupancy at which half-maximal effect occurred indicated that NDMC had an efficacy value equal to 82% of that of the full d-opioid receptor agonist DPDPE, whereas clozapine and the other clozapine metabolite clozapine N-oxide displayed much lower levels of agonist efficacy. NDMC exhibited poor agonist activity and lower affinity at the k-opioid receptor and was inactive at m-opioid and NOP receptors. In NG108-15 cells, NDMC inhibited cyclic AMP formation and stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 by activating the endogenously expressed d-opioid receptor. Moreover, in membranes of different brain regions, NDMC stimulated [ 35 S]GTPgS binding and regulated adenylyl cyclase activity and the effects were potently antagonized by naltrindole. These data demonstrate for the first time that NDMC acts as a selective and efficacious d-opioid receptor agonist and suggest that this unique property may contribute, at least in part, to the clinical actions of the atypical antipsychotic clozapine. Neuropsychopharmacology (2007) 32, 773-785.

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Section: Introductionmentioning

confidence: 90%

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

Onali

Olianas

2006

Neuropsychopharmacol

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“…155,158 The picture is further complicated by other data that suggest that clozapine is also a partial agonist at the M 1 , M 2 , and M 3 receptor. 156,159,160 Although these in vitro studies of the cholinergic properties of clozapine did not yield a clear outcome, N-desmethylclozapine (NDMC), the major metabolite of clozapine, has been shown to be a potent partial agonist at cloned human M 1 receptors. 161 NDMC is the only currently available antipsychotic with M 1 agonist activity.…”

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 99%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

247

211

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Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including preclinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

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“…Several publications have indicated that clozapine and olanzapine have agonist activity, particularly at muscarinic M 4 receptors, but these studies were performed in cells transfected with very high density of muscarinic receptors. [69][70][71] Cells with density approximating estimates of physiological levels and studies in animal tissue in vitro and in vivo have only shown antagonist activities. 72 For example, olanzapine blocked pilocarpine-induced increases in in vivo phosphoinositide hydrolysis in rats, and alone, did not have agonist activity.…”

Section: Interaction Of Antipsychotic Drugs With Muscarinic Receptorsmentioning

confidence: 99%

Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents

Bymaster

Felder

2002

Mol Psychiatry

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The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M 4 receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D 2 receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D 2 receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT 2A receptor antagonism and increasing cortical norepinephrine and dopamine.

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Mixed Agonist–Antagonist Properties of Clozapine at Different Human Cloned Muscarinic Receptor Subtypes Expressed in Chinese Hamster Ovary Cells

Cited by 63 publications

References 29 publications

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

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

Towards a muscarinic hypothesis of schizophrenia

Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents

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