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Revision as of 20:34, 2 May 2010

Desmethylclozapine
File:Desmethylclozapine.png
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
  • 8-chloro-11-piperazin-1-yl-5H-dibenzo[b,e][1,4]diazepine
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.164.220 Edit this at Wikidata
Chemical and physical data
FormulaC17H17ClN4
Molar mass312.80 g/mol g·mol−1
3D model (JSmol)
  • Clc1ccc2Nc4ccccc4C(=N\c2c1)/N3CCNCC3

N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine.[1][2] Interestingly, 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.[4][5][6] It was hypothesized that on account of these unique actions, NDMC might underly 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 due to the fact that 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] In any case, though not useful in the treatment of positive symptoms on its own, it cannot be ruled out that NDMC may contribute to the improvement of cognitive and/or negative symptoms with clozapine.[7]

See also

References

  1. ^ Lovdahl MJ, Perry PJ, Miller DD (1991). "The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography". Therapeutic Drug Monitoring. 13 (1): 69–72. PMID 2057995. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Bablenis E, Weber SS, Wagner RL (1989). "Clozapine: a novel antipsychotic agent". DICP : the Annals of Pharmacotherapy. 23 (2): 109–15. PMID 2658370. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Burstein ES, Ma J, Wong S; et al. (2005). "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. doi:10.1124/jpet.105.092155. PMID 16135699. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Weiner DM, Meltzer HY, Veinbergs I; et al. (2004). "The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine". Psychopharmacology. 177 (1–2): 207–16. doi:10.1007/s00213-004-1940-5. PMID 15258717. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY (2005). "N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 30 (11): 1986–95. doi:10.1038/sj.npp.1300768. PMID 15900318. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Olianas MC, Dedoni S, Ambu R, Onali P (2009). "Agonist activity of N-desmethylclozapine at delta-opioid receptors of human frontal cortex". European Journal of Pharmacology. 607 (1–3): 96–101. doi:10.1016/j.ejphar.2009.02.025. PMID 19239909. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b Bishara D, Taylor D (2008). "Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability". Drugs. 68 (16): 2269–92. PMID 18973393.
  8. ^ Mendoza MC, Lindenmayer JP (2009). "N-desmethylclozapine: is there evidence for its antipsychotic potential?". Clinical Neuropharmacology. 32 (3): 154–7. doi:10.1097/WNF.0b013e31818d46f5. PMID 19483482.
  9. ^ Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S (2007). "Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 32 (7): 1540–9. doi:10.1038/sj.npp.1301279. PMID 17164815. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)


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