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Active metabolite of the drug clozapine
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
^ Lovdahl MJ, Perry PJ, Miller DD (January 1991). "The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography". Therapeutic Drug Monitoring . 13 (1): 69–72.
doi :
10.1097/00007691-199101000-00010 .
PMID
2057995 .
^ Bablenis E, Weber SS, Wagner RL (February 1989). "Clozapine: a novel antipsychotic agent". DICP: The Annals of Pharmacotherapy . 23 (2): 109–15.
doi :
10.1177/106002808902300201 .
PMID
2658370 .
S2CID
36582093 .
^ Burstein ES, Ma J, Wong S, et al. (December 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 .
S2CID
2247093 .
^ Weiner DM, Meltzer HY, Veinbergs I, et al. (December 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 .
S2CID
1024531 .
^ Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY (November 2005).
"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.
doi :
10.1038/sj.npp.1300768 .
PMID
15900318 .
^ Olianas MC, Dedoni S, Ambu R, Onali P (April 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 .
^
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.
doi :
10.2165/0003495-200868160-00002 .
PMID
18973393 .
S2CID
42020114 .
^ 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 .
S2CID
24544110 .
^ Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S (July 2007).
"Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies" . Neuropsychopharmacology . 32 (7): 1540–9.
doi :
10.1038/sj.npp.1301279 .
PMID
17164815 .
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