氯氮平
描述
作用机制
科学研究应用
Pharmacological Profile and Mechanism of Action
Clozapine operates through multiple neurotransmitter systems, impacting serotonin, dopamine, and norepinephrine receptors. This broad action contributes to its efficacy in treating psychotic symptoms and reducing suicidal behavior in patients with schizophrenia.
Key Mechanisms:
- Dopamine Receptor Antagonism: Clozapine primarily antagonizes D2 dopamine receptors, which helps alleviate psychotic symptoms.
- Serotonin Receptor Modulation: It also affects 5-HT2A receptors, which may contribute to its lower risk of extrapyramidal side effects compared to first-generation antipsychotics.
- Anti-Suicidal Properties: Research indicates that clozapine significantly reduces the risk of suicide in patients with schizophrenia and schizoaffective disorder .
Clinical Applications
Clozapine is indicated for:
- Treatment-Resistant Schizophrenia: It is specifically approved for patients who have not responded adequately to at least two other antipsychotic medications. Studies show that clozapine can lead to a 10% reduction in overall mortality among these patients .
- Suicidal Behavior Reduction: Clozapine is effective in decreasing the risk of recurrent suicidal behavior, making it a crucial option for high-risk patients .
- Cognitive Improvement: Some studies suggest that clozapine may enhance cognitive functioning, particularly in working memory, due to its metabolite N-desmethylclozapine .
Efficacy and Safety
A systematic review highlighted the superior efficacy of clozapine compared to both first-generation and second-generation antipsychotics. The meta-analysis included data from 112 studies, confirming clozapine's effectiveness across various psychotic disorders .
Adverse Effects:
Despite its benefits, clozapine is associated with significant risks:
- Severe Neutropenia: Regular monitoring of white blood cell counts is required due to the risk of agranulocytosis.
- Seizures: The risk increases with higher doses.
- Metabolic Syndrome: Weight gain and metabolic changes are common side effects .
Case Study 1: Treatment-Resistant Schizophrenia
A 30-year-old female patient diagnosed with treatment-resistant schizophrenia was treated with clozapine after failing multiple antipsychotic regimens. Following initiation at a low dose (12.5 mg), her symptoms improved significantly over several weeks, demonstrating clozapine's effectiveness in managing severe psychotic symptoms .
Case Study 2: Acute Psychotic Relapse
In another case, a 57-year-old female patient experienced an acute relapse while on clozapine. Adjustments to her medication regimen led to stabilization after a dose reduction from 700 mg/day to a more manageable level. This case illustrates the need for careful monitoring and dose adjustments during treatment .
Data Summary
准备方法
合成路线和反应条件： 氯氮平通过多步合成过程合成，包括 8-氯-11-(4-甲基哌嗪-1-基)-5H-二苯并[b,e][1,4]二氮杂卓与各种试剂反应 .
工业生产方法： 氯氮平的工业生产涉及使用优化的反应条件进行大规模合成，以确保高产率和纯度。 该工艺包括预混合粉末制备、粘合剂制备、造粒、总混合和压片等步骤 . 先进的设备如流化床用于提高造粒和干燥过程的效率 .
化学反应分析
反应类型： 氯氮平会发生各种化学反应，包括氧化、还原和取代 .
常用试剂和条件：
氧化： 通常涉及在受控条件下使用过氧化氢或高锰酸钾等试剂。
还原： 通常使用氢化铝锂或硼氢化钠等试剂。
取代： 通常涉及使用氯或溴等试剂进行卤化反应.
形成的主要产物： 这些反应形成的主要产物包括各种氯氮平衍生物，它们可能具有不同的药理特性 .
相似化合物的比较
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 .
生物活性
Clozapine is an atypical antipsychotic medication primarily used for treatment-resistant schizophrenia (TRS). Its unique pharmacological profile and biological activity distinguish it from other antipsychotics, making it a subject of extensive research. This article delves into the biological activity of clozapine, its mechanisms of action, clinical findings, and relevant case studies.
Clozapine exhibits a complex pharmacological profile, interacting with multiple neurotransmitter systems. Notably, it has a low affinity for dopamine D2 receptors compared to first-generation antipsychotics. Instead, clozapine acts as an antagonist at various receptors:
| Receptor Type | Binding Affinity (Ki) |
|---|---|
| Histamine H1 | 1.1 nM |
| Adrenergic α1A | 1.6 nM |
| Serotonin 5-HT6 | 4 nM |
| Serotonin 5-HT2A | 5.4 nM |
| Muscarinic M1 | 6.2 nM |
| Dopamine D4 | 24 nM |
| Dopamine D2 | 160 nM |
This diverse receptor binding profile suggests that clozapine's efficacy in treating TRS may stem from its ability to modulate neurotransmission across multiple pathways, including serotonergic and glutamatergic systems .
Clinical Efficacy and Patient Experiences
Clozapine is particularly effective in patients who do not respond to other antipsychotic treatments. A systematic review involving 1,487 patients indicated that most reported positive experiences with clozapine, highlighting significant symptom improvement and overall satisfaction despite some common side effects such as hypersalivation and weight gain .
Case Study: Cognitive Effects
A notable case study examined the cognitive effects of clozapine on a patient with TRS. The findings suggested that cognitive impairment could be dose-dependent, emphasizing the need for careful monitoring of dosage to optimize therapeutic outcomes while minimizing adverse effects .
Neurobiological Effects
Research indicates that clozapine influences neurobiological functioning in patients with TRS. For instance, a study by Molina et al. demonstrated that clozapine treatment was associated with reductions in prefrontal cortical metabolic activity, which correlated with improvements in both positive and negative symptoms of schizophrenia . This suggests that alterations in brain metabolism may play a crucial role in the drug's therapeutic effects.
Metabolite Activity
Clozapine is metabolized into several active metabolites, including N-desmethylclozapine. Studies have shown that this metabolite retains biological activity and can influence Fos protein expression in specific brain regions, mirroring the effects of clozapine itself . This finding underscores the importance of considering both the parent compound and its metabolites when evaluating clozapine's overall pharmacological impact.
Safety Profile
Concerns regarding the safety of clozapine have been addressed in recent studies. A large cohort study conducted by researchers at the University of Hong Kong found that the risk of developing blood cancer associated with clozapine use is very low—less than six cases per 10,000 patients treated annually . These findings support the continued use of clozapine in clinical practice while emphasizing the importance of regular blood monitoring to mitigate risks.
属性
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 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the 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. | |
| 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
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
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
体外研究产品的免责声明和信息
请注意，BenchChem 上展示的所有文章和产品信息仅供信息参考。 BenchChem 上可购买的产品专为体外研究设计，这些研究在生物体外进行。体外研究，源自拉丁语 "in glass"，涉及在受控实验室环境中使用细胞或组织进行的实验。重要的是要注意，这些产品没有被归类为药物或药品，他们没有得到 FDA 的批准，用于预防、治疗或治愈任何医疗状况、疾病或疾病。我们必须强调，将这些产品以任何形式引入人类或动物的身体都是法律严格禁止的。遵守这些指南对确保研究和实验的法律和道德标准的符合性至关重要。
