Systematic (IUPAC) name
Clinical data
Legal status
  • Uncontrolled
Routes Oral
CAS number
ATC code None
Chemical data
Formula C17H17ClN4 
Mol. mass 312.80 g/mol

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] 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 efficacy of clozapine on cognitive and/or negative symptoms.[7]

See also


  1. ^ 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.  
  2. ^ Bablenis E, Weber SS, Wagner RL (February 1989). "Clozapine: a novel antipsychotic agent". DICP : the Annals of Pharmacotherapy 23 (2): 109–15.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  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.  
  8. ^ Mendoza MC, Lindenmayer JP (2009). "N-desmethylclozapine: is there evidence for its antipsychotic potential?". Clinical Neuropharmacology 32 (3): 154–7.  
  9. ^ 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.