Chemistry:Desmethylclozapine
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| Routes of administration | Oral |
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| Formula | C17H17ClN4 |
| Molar mass | 312.80 g·mol−1 |
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N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine.[1][2] Unlike clozapine, it possesses intrinsic activity at the D2/D3 receptors, and acts as a weak partial agonist at these sites similarly to aripiprazole and bifeprunox.[3] Notably, NDMC has also been shown to act as a potent and efficacious agonist at the M1 and δ-opioid receptors, unlike clozapine as well.[4][5][6] It was hypothesized that on account of these unique actions, NDMC might underlie the clinical superiority of clozapine over other antipsychotics. However, clinical trials found NMDC itself ineffective in the treatment of schizophrenia.[7][8] This may be because it possesses relatively low D2/D3 occupancy compared to 5-HT2 (<15% versus 64–79% at a dose of 10–60 mg/kg s.c. in animal studies).[9] Albeit not useful in the treatment of positive symptoms on its own, it cannot be ruled out that NDMC may contribute to the efficacy of clozapine on cognitive and/or negative symptoms.[7]
See also
References
- ↑ "The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography". Therapeutic Drug Monitoring 13 (1): 69–72. January 1991. doi:10.1097/00007691-199101000-00010. PMID 2057995.
- ↑ "Clozapine: a novel antipsychotic agent". DICP: The Annals of Pharmacotherapy 23 (2): 109–15. February 1989. doi:10.1177/106002808902300201. PMID 2658370.
- ↑ "Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist". The Journal of Pharmacology and Experimental Therapeutics 315 (3): 1278–87. December 2005. doi:10.1124/jpet.105.092155. PMID 16135699.
- ↑ "The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine". Psychopharmacology 177 (1–2): 207–16. December 2004. doi:10.1007/s00213-004-1940-5. PMID 15258717.
- ↑ "N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors". Neuropsychopharmacology 30 (11): 1986–95. November 2005. doi:10.1038/sj.npp.1300768. PMID 15900318.
- ↑ "Agonist activity of N-desmethylclozapine at delta-opioid receptors of human frontal cortex". European Journal of Pharmacology 607 (1–3): 96–101. April 2009. doi:10.1016/j.ejphar.2009.02.025. PMID 19239909.
- ↑ 7.0 7.1 "Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability". Drugs 68 (16): 2269–92. 2008. doi:10.2165/0003495-200868160-00002. PMID 18973393.
- ↑ "N-desmethylclozapine: is there evidence for its antipsychotic potential?". Clinical Neuropharmacology 32 (3): 154–7. 2009. doi:10.1097/WNF.0b013e31818d46f5. PMID 19483482.
- ↑ "Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies". Neuropsychopharmacology 32 (7): 1540–9. July 2007. doi:10.1038/sj.npp.1301279. PMID 17164815.
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