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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 でるた -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]
^ 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 .
H1
Agonists Antagonists
Others: Atypical antipsychotics (e.g., aripiprazole , asenapine , brexpiprazole , brilaroxazine , clozapine , iloperidone , olanzapine , paliperidone , quetiapine , risperidone , ziprasidone , zotepine )
Phenylpiperazine antidepressants (e.g., hydroxynefazodone , nefazodone , trazodone , triazoledione )
Tetracyclic antidepressants (e.g., amoxapine , loxapine , maprotiline , mianserin , mirtazapine , oxaprotiline )
Tricyclic antidepressants (e.g., amitriptyline , butriptyline , clomipramine , desipramine , dosulepin (dothiepin) , doxepin , imipramine , iprindole , lofepramine , nortriptyline , protriptyline , trimipramine )
Typical antipsychotics (e.g., chlorpromazine , flupenthixol , fluphenazine , loxapine , perphenazine , prochlorperazine , thioridazine , thiothixene )
H2
H3
H4
mAChRs Tooltip Muscarinic acetylcholine receptors
Agonists Antagonists
3-Quinuclidinyl benzilate
4-DAMP
Aclidinium bromide (+formoterol )
Abediterol
AF-DX 250
AF-DX 384
Ambutonium bromide
Anisodamine
Anisodine
Antihistamines (first-generation) (e.g., brompheniramine , buclizine , captodiame , chlorphenamine (chlorpheniramine) , cinnarizine , clemastine , cyproheptadine , dimenhydrinate , dimetindene , diphenhydramine , doxylamine , meclizine , mequitazine , perlapine , phenindamine , pheniramine , phenyltoloxamine , promethazine , propiomazine , triprolidine )
AQ-RA 741
Atropine
Atropine methonitrate
Atypical antipsychotics (e.g., clozapine , fluperlapine , olanzapine (+fluoxetine ), rilapine , quetiapine , tenilapine , zotepine )
Benactyzine
Benzatropine (benztropine)
Benzilone
Benzilylcholine mustard
Benzydamine
Bevonium
BIBN 99
Biperiden
Bornaprine
Camylofin
CAR-226,086
CAR-301,060
CAR-302,196
CAR-302,282
CAR-302,368
CAR-302,537
CAR-302,668
Caramiphen
Cimetropium bromide
Clidinium bromide
Cloperastine
CS-27349
Cyclobenzaprine
Cyclopentolate
Darifenacin
DAU-5884
Desfesoterodine
Dexetimide
DIBD
Dicycloverine (dicyclomine)
Dihexyverine
Difemerine
Diphemanil metilsulfate
Ditran
Drofenine
EA-3167
EA-3443
EA-3580
EA-3834
Emepronium bromide
Etanautine
Etybenzatropine (ethybenztropine)
Fenpiverinium
Fentonium bromide
Fesoterodine
Flavoxate
Glycopyrronium bromide (+beclometasone/formoterol , +indacaterol , +neostigmine )
Hexahydrodifenidol
Hexahydrosiladifenidol
Hexbutinol
Hexocyclium
Himbacine
HL-031,120
Homatropine
Imidafenacin
Ipratropium bromide (+salbutamol )
Isopropamide
J-104,129
Hyoscyamine
Mamba toxin 3
Mamba toxin 7
Mazaticol
Mebeverine
Meladrazine
Mepenzolate
Methantheline
Methoctramine
Methylatropine
Methylhomatropine
Methylscopolamine
Metixene
Muscarinic toxin 7
N-Ethyl-3-piperidyl benzilate
N-Methyl-3-piperidyl benzilate
Nefopam
Octatropine methylbromide (anisotropine methylbromide)
Orphenadrine
Otenzepad (AF-DX 116)
Otilonium bromide
Oxapium iodide
Oxitropium bromide
Oxybutynin
Oxyphencyclimine
Oxyphenonium bromide
PBID
PD-102,807
PD-0298029
Penthienate
Pethidine
pFHHSiD
Phenglutarimide
Phenyltoloxamine
Pipenzolate bromide
Piperidolate
Pirenzepine
Piroheptine
Pizotifen
Poldine
Pridinol
Prifinium bromide
Procyclidine
Profenamine (ethopropazine)
Propantheline bromide
Propiverine
Quinidine
3-Quinuclidinyl thiochromane-4-carboxylate
Revefenacin
Rociverine
RU-47,213
SCH-57,790
SCH-72,788
SCH-217,443
Scopolamine (hyoscine)
Scopolamine butylbromide (hyoscine butylbromide)
Silahexacyclium
Sofpironium bromide
Solifenacin
SSRIs Tooltip Selective serotonin reuptake inhibitors (e.g., femoxetine , paroxetine )
Telenzepine
Terodiline
Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin , mirtazapine )
Tiemonium iodide
Timepidium bromide
Tiotropium bromide
Tiquizium bromide
Tofenacin
Tolterodine
Tricyclic antidepressants (e.g., amitriptyline (+perphenazine ), amitriptylinoxide , butriptyline , cidoxepin , clomipramine , desipramine , desmethyldesipramine , dibenzepin , dosulepin (dothiepin) , doxepin , imipramine , lofepramine , nitroxazepine , northiaden (desmethyldosulepin) , nortriptyline , protriptyline , quinupramine , trimipramine )
Tridihexethyl
Trihexyphenidyl
Trimebutine
Tripitamine (tripitramine)
Tropacine
Tropatepine
Tropicamide
Trospium chloride
Typical antipsychotics (e.g., chlorpromazine , chlorprothixene , cyamemazine (cyamepromazine) , loxapine , mesoridazine , thioridazine )
Umeclidinium bromide (+vilanterol )
WIN-2299
Xanomeline
Zamifenacin
Precursors (and prodrugs )