The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine?s actions?

Davies, Marilyn A.; Compton-Toth, Beth A.; Hufeisen, Sandra J.; Meltzer, Herbert Y.; Roth, Bryan L.

doi:10.1007/s00213-004-2017-1

Cited by 115 publications

(81 citation statements)

References 62 publications

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“…We also confirmed cell-type differences in the effects of pirenzepine and darifenacin on oxo-M-induced current responses, indicating that the contribution of M 1 receptors to the muscarinic responses is evident only in excitatory neurons. These results strongly suggest that the agonist activity of NDMC depends on the M 1 , rather than M 3 , subtype, in agreement with some biochemical studies reporting that NDMC exhibits a partial agonist profile at M 1 receptors (Davies et al, 2005;Gregory et al, 2007;Weiner et al, 2004).…”

Section: Discussionsupporting

confidence: 92%

“…Among the muscarinic receptor subtypes (M 1 -M 5 ), much attention has been given to M 1 receptors, because it is implicated in learning and memory processes (Anagnostaras et al, 2003;Shirey et al, 2009). Biochemical studies demonstrated that NDMC exhibits a partial agonist profile at human recombinant M 1 receptors (Davies et al, 2005), which seems to be unique and not shared by any other antipsychotics. However, direct electrophysiological evidence showing the ability of NDMC to activate native M 1 receptors in intact neurons is poor.…”

Section: Introductionmentioning

confidence: 93%

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

et al. 2016

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antagonist darifenacin was effective in both types of neurons. Muscarinic agonist activity of NDMC was higher than that of clozapine, higher in excitatory neurons than in inhibitory neurons, sensitive to pirenzepine, and partially masked when co-applied with clozapine. Muscarinic antagonist activity of clozapine as well as NDMC was not different between excitatory and inhibitory neurons, but clozapine was more effective than NDMC.These results demonstrate that NDMC has the ability to activate native M 1 receptors expressed in hippocampal excitatory neurons, but its agonist activity might be limited in clozapine-treated patients because of the presence of excessive clozapine with muscarinic 4 antagonist activity.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 93%

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

et al. 2016

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“…Previous studies have described partial agonist effects of NDMC at the cloned M 1 -M 5 muscarinic receptors (Sur et al, 2003;Weiner et al, 2004;Davies et al, 2005) and D 2 and D 3 DA receptors (Burstein et al, 2005) with potencies generally comparable to those observed in CHO/DOR cells (pEC 50 (Davies et al, 2005) and of 6.94 (Sur et al, 2003) and phosphoinositide hydrolysis with a pEC 50 of 6.7 (Weiner et al, 2004). At D 2 and D 3 DA receptors, NDMC displayed agonist activity equal to 35 and 50% of that of pergolide at the concentration of 20 and 30 nM, respectively (Burstein et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…A similar property has recently been demonstrated for NDMC. Thus, in cell lines expressing the cloned human muscarinic receptor subtypes NDMC has been found to act as a partial agonist with potencies and efficacies higher than those of the parent drug (Sur et al, 2003;Weiner et al, 2004;Davies et al, 2005). In CA1 hippocampal neurons, NDMC was found to potentiate NMDA-mediated currents (Sur et al, 2003) and to induce phosphorylation of extracellular signal-regulated kinases (ERK) by activating muscarinic M 1 receptors (Weiner et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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“…However, the reason for its unique therapeutic efficacy is still not well understood. Recent clinical and preclinical data have raised the possibility of an important therapeutic role of clozapine's major metabolite N-desmethylclozapine (NDMC) (Sur et al, 2003;Weiner et al, 2004;Burstein et al, 2005;Davies et al, 2005;Li et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine?s actions?

Cited by 115 publications

References 62 publications

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

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

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

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

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