Desmethylclozapine

{{Drugbox

| IUPAC_name = 8-chloro-11-piperazin-1-yl-5H-dibenzo[b,e][1,4]diazepine

| image = Desmethylclozapine.svg

| alt = Skeletal formula of desmethylclozapine

| image2 = Desmethylclozapine 3D spacefill.png

| alt2 = Space-filling model of the desmethylclozapine molecule

| tradename =

| pregnancy_category =

| legal_status = Uncontrolled

| routes_of_administration = Oral

| bioavailability =

| metabolism =

| elimination_half-life =

| excretion =

| IUPHAR_ligand = 333

| CAS_number = 6104-71-8

| ATC_prefix = none

| ATC_suffix =

| PubChem = 2820

| ChemSpiderID = 14126465

| UNII = 1I9001LWY8

| ChEMBL = 845

| synonyms =

| C=17 | H=17 | Cl=1 | N=4

| smiles = Clc1ccc2Nc4ccccc4C(=N\c2c1)/N3CCNCC3

}}

N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine.{{cite journal |vauthors=Lovdahl MJ, Perry PJ, Miller DD | title = The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography | journal = Therapeutic Drug Monitoring | volume = 13 | issue = 1 | pages = 69–72 |date=January 1991 | pmid = 2057995 | doi = 10.1097/00007691-199101000-00010}}{{cite journal |vauthors=Bablenis E, Weber SS, Wagner RL | title = Clozapine: a novel antipsychotic agent | journal = DICP: The Annals of Pharmacotherapy | volume = 23 | issue = 2 | pages = 109–15 |date=February 1989 | pmid = 2658370 | doi = 10.1177/106002808902300201| s2cid = 36582093 }}

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.{{cite journal |vauthors=Burstein ES, Ma J, Wong S, etal | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 315 | issue = 3 | pages = 1278–87 |date=December 2005 | pmid = 16135699 | doi = 10.1124/jpet.105.092155 | s2cid = 2247093 }} Notably, NDMC has also been shown to act as a potent and efficacious agonist at the muscarinic acetylcholine M₁ receptor and the δ-opioid receptor, unlike clozapine as well.{{cite journal |vauthors=Weiner DM, Meltzer HY, Veinbergs I, etal | title = The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine | journal = Psychopharmacology | volume = 177 | issue = 1–2 | pages = 207–16 |date=December 2004 | pmid = 15258717 | doi = 10.1007/s00213-004-1940-5 | s2cid = 1024531 }}{{cite journal |vauthors=Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY | title = N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors | journal = Neuropsychopharmacology | volume = 30 | issue = 11 | pages = 1986–95 |date=November 2005 | pmid = 15900318 | doi = 10.1038/sj.npp.1300768 | doi-access = free }}{{cite journal |vauthors=Olianas MC, Dedoni S, Ambu R, Onali P | title = Agonist activity of N-desmethylclozapine at delta-opioid receptors of human frontal cortex | journal = European Journal of Pharmacology | volume = 607 | issue = 1–3 | pages = 96–101 |date=April 2009 | pmid = 19239909 | doi = 10.1016/j.ejphar.2009.02.025 }} It is a moderate-efficacy partial agonist of the muscarinic acetylcholine M₁ and M₂ receptors, a very weak partial agonist or antagonist of the M₃ receptor, and a silent antagonist of the M₄ receptor.{{cite journal | vauthors = Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, Brandish PE, Pettibone DJ, Scolnick EM, Conn PJ | title = N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 23 | pages = 13674–13679 | date = November 2003 | pmid = 14595031 | pmc = 263872 | doi = 10.1073/pnas.1835612100 | doi-access = free | url = }} It also binds with high affinity to the M₅ receptor, but its intrinsic activity was not reported for this receptor.

It was hypothesized that on account of its 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.{{cite journal |vauthors=Bishara D, Taylor D | title = Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability | journal = Drugs | volume = 68 | issue = 16 | pages = 2269–92 | year = 2008 | pmid = 18973393 | doi = 10.2165/0003495-200868160-00002| s2cid = 42020114 }}{{cite journal |vauthors=Mendoza MC, Lindenmayer JP | title = N-desmethylclozapine: is there evidence for its antipsychotic potential? | journal = Clinical Neuropharmacology | volume = 32 | issue = 3 | pages = 154–7 | year = 2009 | pmid = 19483482 | doi = 10.1097/WNF.0b013e31818d46f5 | s2cid = 24544110 }} This may be because it possesses relatively low D₂/D₃ occupancy compared to the 5-HT₂ receptor (<15% versus 64–79% at a dose of 10–60 mg/kg s.c. in animal studies).{{cite journal |vauthors=Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S | title = Evaluation of N-desmethylclozapine as a potential antipsychotic--preclinical studies | journal = Neuropsychopharmacology | volume = 32 | issue = 7 | pages = 1540–9 |date=July 2007 | pmid = 17164815 | doi = 10.1038/sj.npp.1301279 | doi-access = free }}

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.