Clozapine (CHEM002181)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesTargets (35)XML
Record Information
Version1.0
Creation Date2009-07-21 20:26:42 UTC
Update Date2026-05-14 16:36:36 UTC
Accession NumberCHEM002181
Identification
Common NameClozapine
ClassSmall Molecule
DescriptionA tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.
Contaminant Sources
  • HMDB Contaminants - Urine
  • STOFF IDENT Compounds
  • Suspected Compounds
  • T3DB toxins
  • ToxCast & Tox21 Chemicals
Contaminant Type
  • Amine
  • Antipsychotic Agent
  • Drug
  • GABA Antagonist
  • Human Neurotoxin
  • Metabolite
  • Organic Compound
  • Organochloride
  • Serotonin Antagonist
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
ValueSource
ClozapinChEBI
ClozapinaChEBI
ClozapinumChEBI
ClozarilKegg
LeponexHMDB
Chemical FormulaC18H19ClN4
Average Molecular Mass326.823 g/mol
Monoisotopic Mass326.130 g/mol
CAS Registry Number5786-21-0
IUPAC Name6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,9,11,13-heptaene
Traditional Nameclozapine
SMILESCN1CCN(CC1)C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12
InChI IdentifierInChI=1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3
InChI KeyQZUDBNBUXVUHMW-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as dibenzodiazepines. Dibenzodiazepines are compounds containing a dibenzodiazepine moiety, which consists of two benzene connected by diazepine ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzodiazepines
Sub ClassDibenzodiazepines
Direct ParentDibenzodiazepines
Alternative Parents
Substituents
  • Dibenzodiazepine
  • 1,4-benzodiazepine
  • N-methylpiperazine
  • N-alkylpiperazine
  • Aryl chloride
  • Aryl halide
  • 1,4-diazinane
  • Imidolactam
  • Piperazine
  • Benzenoid
  • Tertiary amine
  • Tertiary aliphatic amine
  • Amidine
  • Secondary amine
  • Organic 1,3-dipolar compound
  • Azacycle
  • Carboxylic acid amidine
  • Propargyl-type 1,3-dipolar organic compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Organic nitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point183-184°C
Boiling PointNot Available
Solubility11.8 mg/L
Predicted Properties
PropertyValueSource
Water Solubility0.19 g/LALOGPS
logP3.67ALOGPS
logP3.4ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)15.9ChemAxon
pKa (Strongest Basic)7.35ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area30.87 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity97.36 m³·mol⁻¹ChemAxon
Polarizability35.77 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-06r5-9064000000-0f31b1de88be42ac8381Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-00b9-0298000000-50d2ee0b52827fd1aee3Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-00di-2690000000-daaa74a4f85f5e8b5926Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0090000000-bc2ca4d5a76a5facf897Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-004i-0009000000-986bc19f7e7e8602d005Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00b9-0049000000-d6315d4aeb74c251e939Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0090000000-27fd28450826291cc8c6Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0290000000-474b25ea27690471db0fSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-0970000000-a58015260aaddb4245bdSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-0930000000-3ccfd048a34fdb4f594fSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-004i-0009000000-7df53c42e3b1618bfdecSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-004i-0049000000-7522cc8ebf988effc792Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0090000000-bd138be4ae488c201ed3Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0190000000-68c8b78f304c38b7b7b5Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-0980000000-a9dd724f32c02059c510Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0006-0930000000-61c0f65f163824ddd594Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0090000000-da747a0572aa2c21683fSpectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-002f-0930000000-614883dbe075268cf23aSpectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-00b9-0298000000-50d2ee0b52827fd1aee3Spectrum
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-00di-2690000000-daaa74a4f85f5e8b5926Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-004i-0009000000-b771968b218f574a2031Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-1049000000-24dab1e16fa5778e3f05Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-004i-2190000000-6b669cd26b101d106f1cSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0009000000-178d40f752b4d092a8a6Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0029000000-5b7197f427b8cfdcdac2Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-4290000000-33f870d86d2adcc8f049Spectrum
Toxicity Profile
Route of ExposureOral; rapid and almost complete.
Mechanism of ToxicityThe mechanism of action of Clozapine, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Atypical antipsychotic drugs such as clozapine have been proposed to block the 5HT2 and D2 receptors at therapeutic doses as evidenced by blockage in accelerating levels of growth hormone and cortisol secretion. The antipsychotic activity of clozapine is assumed to be the cause of D2 blockade while interacting with other receptors as well. With regards to mode of action in blocking dopaminergic receptors, clozapine exhibits higher affinity for D4 compared to the D2 receptor subtype. In addition, D1 antagonistic activity of clozapine enhances dopaminergic activity by increased extracellular brain dopamine concentrations specifically in the prefrontal cortex which is believed to explain its efficacy against negative symptoms generally observed in schizophrenia when using other drugs. Interestingly, clozapine has not been able to block arousal behavior which is the case when using other dopamine agonists after prolonged treatment. Interaction of clozapine with the immune system has also been found important when using this drug. Neutrophil apoptosis otherwise known as agranulocytosis was detected after administration of clopazine alone and bioactived clozapine to nitrenium ion at supratherapeutic and therapeutic levels, respectively. At supratherapeutic concentrations, clozapine can be toxic due to the drug itself or its stable metabolite products. At therapeutic levels however, the chemically reactive nitrenium ion is believed to bound to cellular protein, deplete intracellular GSH, and lead to final polymorphonuclear (PMN) and mononuclear leukocyte cytotoxicity in vitro. Agranulocytosis induced by bioactived clozapine can be inhibited by using antioxidants and genistein. PMN apoptosis is believed to be achieved by decelerating the life span of circulating cells after clozapine administration. Clozapine has also shown to interact with GABA receptors. Clozapine is able to induce release of glutamate and D-serine and decrease expression of glutamate transporters in astrocytic cell cultures with no neurons.
MetabolismHepatic Route of Elimination: Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. Half Life: 8 hours (range 4-12 hours)
Toxicity ValuesNot Available
Lethal DoseFatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. (13)
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use in patients with treatment-resistant schizophrenia.
Minimum Risk LevelNot Available
Health EffectsClozapine may cause side effects; most are minor, although some are serious and potentially fatal. Common side effects include extreme constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain. The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Clozapine also carries five black box warnings, including warnings for agranulocytosis, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures. Lowering of the seizure threshold may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for orthostatic hypotension and other adverse cardiovascular side effects. Many male patients have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides. (Wikipedia)
SymptomsNot Available
TreatmentEstablish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia. There are no specific antidotes for Clozapine. (13)
Concentrations
Not Available
DrugBank IDDB00363
HMDB IDHMDB0014507
FooDB IDNot Available
Phenol Explorer IDNot Available
KNApSAcK IDNot Available
BiGG IDNot Available
BioCyc IDNot Available
METLIN IDNot Available
PDB IDNot Available
Wikipedia LinkClozapine
Chemspider ID10442628
ChEBI ID3766
PubChem Compound IDNot Available
Kegg Compound IDC06924
YMDB IDNot Available
ECMDB IDNot Available
References
Synthesis Reference

Schmutz, J. and Hunziker, F.; US. Patent 3,539,573; November 10, 1970 .

MSDSNot Available
General References
1. https://www.ncbi.nlm.nih.gov/pubmed/?term=18690109
2. https://www.ncbi.nlm.nih.gov/pubmed/?term=18766167
3. https://www.ncbi.nlm.nih.gov/pubmed/?term=20825390
4. https://www.ncbi.nlm.nih.gov/pubmed/?term=24219174
5. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA: Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993 Jul 15;329(3):162-7.
6. Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW: Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry. 1999 Jan;60(1):36-40.
7. Naheed M, Green B: Focus on clozapine. Curr Med Res Opin. 2001;17(3):223-9.
8. Vaddadi KS, Soosai E, Vaddadi G: Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol. 2003 Mar;55(3):307-9.