Clozapina
Descripción general
Descripción
Clozapine is an atypical antipsychotic medication primarily used to treat schizophrenia and schizoaffective disorder in patients who have not responded adequately to other antipsychotic treatments . It was the first of the second-generation antipsychotics and is known for its efficacy in reducing suicidal behavior in patients with schizophrenia . Clozapine is also used to treat psychosis in Parkinson’s disease .
Mecanismo De Acción
Target of Action
Clozapine is an atypical or second-generation antipsychotic drug . It primarily targets various neuroreceptors, including dopamine type 4 (D4) receptors, serotonin type 2 (5-HT2A) receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors . It has a high dissociation constant for D2, which is even higher than dopamine . Clozapine has much higher antagonistic activity on cortical and limbic dopamine D4 than D2 receptors . It also antagonizes 5HT2 serotonergic receptor subtypes (5HT2A & 5HT2C) and adrenergic (α1), histamine (H1), and muscarinic receptors (M1) .
Mode of Action
The therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors . Clozapine’s interaction with its targets results in fewer extrapyramidal side effects, especially tardive dyskinesia . Its promiscuity toward the muscarinic and adrenergic receptors can result in other side effects, notably gastrointestinal hypomotility and orthostatic hypotension .
Biochemical Pathways
Clozapine undergoes extensive hepatic metabolism with the main routes being demethylation to N-desmethylclozapine and oxidation to clozapine n-oxide . In vitro experiments suggest that CYP3A4 accounts for around 70% of clozapine clearance, CYP1A2 around 15%, and 5% or less for each of CYP2C19, CYP2C8 and FMO3 .
Pharmacokinetics
Clozapine’s pharmacokinetic properties are characterized by its absorption, distribution, metabolism, and excretion (ADME). It is absorbed and distributed in the body, metabolized primarily in the liver by cytochrome P450 (CYP) enzymes, and excreted . The majority of the interactions with clozapine are reported to be mediated by CYP enzymes .
Result of Action
Clozapine’s action results in a range of molecular and cellular effects. It has been shown to affect metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells . It also induces mitohormesis and metabolic reprogramming in human blood cells . Moreover, treatment with clozapine-exposed extracellular vesicles induced an inflammasome-dependent response, supporting a potential role for extracellular vesicles in immune activation .
Action Environment
Environmental factors can influence the action, efficacy, and stability of clozapine. For instance, smoking cessation has been reported to increase clozapine levels . Furthermore, the drug’s mechanism and its relative efficacy remain inadequately defined due to various patient-specific factors . Therefore, clinicians must maintain increased clinical vigilance for adverse side effects when clozapine is combined with other medications .
Aplicaciones Científicas De Investigación
Clozapine has a wide range of applications in scientific research:
Métodos De Preparación
Synthetic Routes and Reaction Conditions: Clozapine is synthesized through a multi-step process involving the reaction of 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine with various reagents .
Industrial Production Methods: Industrial production of clozapine involves large-scale synthesis using optimized reaction conditions to ensure high yield and purity. The process includes steps such as premixed powder preparation, adhesive preparation, granulation, total mixing, and tabletting . Advanced equipment like fluidized beds are used to improve the efficiency of granulation and drying processes .
Análisis De Reacciones Químicas
Types of Reactions: Clozapine undergoes various chemical reactions, including oxidation, reduction, and substitution .
Common Reagents and Conditions:
Oxidation: Typically involves reagents like hydrogen peroxide or potassium permanganate under controlled conditions.
Reduction: Commonly uses reagents such as lithium aluminum hydride or sodium borohydride.
Substitution: Often involves halogenation reactions using reagents like chlorine or bromine.
Major Products Formed: The major products formed from these reactions include various clozapine derivatives, which can have different pharmacological properties .
Comparación Con Compuestos Similares
Quetiapine: Another atypical antipsychotic with a similar receptor binding profile but different side effects and efficacy.
Aripiprazole: Known for its partial agonist activity at dopamine receptors, offering a different mechanism of action compared to clozapine.
Olanzapine: Shares some pharmacological properties with clozapine but has a higher risk of metabolic side effects.
Uniqueness of Clozapine: Clozapine is unique due to its superior efficacy in treatment-resistant schizophrenia and its ability to reduce suicidal behavior . It also has a lower risk of extrapyramidal side effects compared to first-generation antipsychotics .
Propiedades
IUPAC Name |
3-chloro-6-(4-methylpiperazin-1-yl)-11H-benzo[b][1,4]benzodiazepine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=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 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
QZUDBNBUXVUHMW-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1CCN(CC1)C2=NC3=C(C=CC(=C3)Cl)NC4=CC=CC=C42 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C18H19ClN4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID5022855, DTXSID401020663 |
Source
|
| Record name | Clozapine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID5022855 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 8-Chloro-11-(4-methyl-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID401020663 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
326.8 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Clozapine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014507 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Solubility wt/wt at 25 °C: water <0.01, Solubility wt/wt at 25 °C: Acetone >5; acetonitrile 1.9; chloroform >20; ethhyl acetate >5; absolute ethanol 4.0, 1.86e-01 g/L |
Source
|
| Record name | Clozapine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00363 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | CLOZAPINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6478 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Clozapine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014507 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Clozapine's antipsychotic action is likely mediated through a combination of antogistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms., Clozapine is classified as an 'atypical' antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although clozapine does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors. |
Source
|
| Record name | Clozapine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00363 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | CLOZAPINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6478 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Yellow crystals from acetone-petroleum ether | |
CAS No. |
5786-21-0, 1333667-72-3 |
Source
|
| Record name | Clozapine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=5786-21-0 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Clozapine [USAN:USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0005786210 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Clozapine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00363 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | clozapine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=757429 | |
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| Record name | Clozapine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID5022855 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 8-Chloro-11-(4-methyl-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID401020663 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Clozapine | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.024.831 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | CLOZAPINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/J60AR2IKIC | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | CLOZAPINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6478 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Clozapine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014507 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
183-184 °C, 183 - 184 °C |
Source
|
| Record name | Clozapine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00363 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | CLOZAPINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6478 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Clozapine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014507 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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