Clomipramine
Overview
Description
Clomipramine is a tricyclic antidepressant primarily used to treat obsessive-compulsive disorder. It is also effective in treating other conditions such as major depressive disorder, panic disorder, and chronic pain. This compound was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy and is sold under the brand name Anafranil among others .
Mechanism of Action
Target of Action
Clomipramine, a tricyclic antidepressant (TCA), primarily targets the serotonin and norepinephrine reuptake transporters . These transporters are responsible for the reabsorption of serotonin and norepinephrine into the presynaptic neuron after they have completed their function of transmitting a neural impulse. By inhibiting these transporters, this compound increases the levels of serotonin and norepinephrine in the synaptic cleft, enhancing their neurotransmission .
Mode of Action
This compound acts as a potent inhibitor of serotonin reuptake and a less potent inhibitor of norepinephrine reuptake . It binds to the serotonin and norepinephrine transporters, blocking their action, which leads to an increased concentration of these neurotransmitters in the synaptic cleft . This results in prolonged neurotransmitter action on the post-synaptic receptors, enhancing serotonergic and noradrenergic neurotransmission .
Biochemical Pathways
The enhanced serotonergic and noradrenergic neurotransmission resulting from this compound’s action can affect various biochemical pathways. For instance, it has been reported that this compound can interfere with the autophagic flux, a crucial cellular degradation pathway . This interference can lead to changes in the metabolomic pathways associated with the pathophysiology of depression .
Pharmacokinetics
This compound is rapidly absorbed from the gastrointestinal tract and is extensively metabolized in the liver, primarily by the CYP2D6 enzyme, to its active metabolite, desmethylthis compound . The bioavailability of this compound is approximately 50% . It has a high protein binding capacity of 96-98% . The elimination half-life of this compound is 19-37 hours, and that of desmethylthis compound is 54-77 hours . It is excreted in the urine (51-60%) and feces (24-32%) .
Result of Action
The increased levels of serotonin and norepinephrine in the synaptic cleft due to this compound’s action can lead to various molecular and cellular effects. These include down-regulation of cerebral cortical β-adrenergic receptors and sensitization of post-synaptic serotonergic receptors with chronic use . This can result in mood elevation in depressed individuals . Moreover, this compound has been found to inhibit neuronal autophagic flux, which can have significant implications for cellular viability and function .
Action Environment
Environmental factors can influence the action, efficacy, and stability of this compound. For instance, factors such as pollution and smoking can enhance the risk of negative outcomes . Furthermore, the route of administration can affect the drug’s action. For example, intranasal administration of this compound has been associated with more significant changes in the metabolites composition in the frontal cortex compared to other routes .
Preparation Methods
Synthetic Routes and Reaction Conditions: Clomipramine is synthesized through a multi-step process starting from iminodibenzyl. The key steps involve:
Chlorination: Iminodibenzyl is chlorinated to form 3-chloroiminodibenzyl.
Reduction: The chlorinated product is reduced to 3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepine.
Alkylation: The final step involves alkylation with 3-dimethylaminopropyl chloride to yield this compound.
Industrial Production Methods: Industrial production of this compound typically follows the same synthetic route but on a larger scale. The process involves stringent control of reaction conditions to ensure high purity and yield. The final product is often converted to its hydrochloride salt form for stability and ease of formulation .
Chemical Reactions Analysis
Types of Reactions: Clomipramine undergoes several types of chemical reactions, including:
Oxidation: this compound can be oxidized to form its N-oxide derivative.
Reduction: The compound can be reduced to its desmethyl metabolite, desmethylthis compound.
Substitution: Halogenation and alkylation reactions can modify the this compound molecule.
Common Reagents and Conditions:
Oxidation: Hydrogen peroxide or peracids are commonly used.
Reduction: Lithium aluminum hydride or sodium borohydride are typical reducing agents.
Substitution: Halogenating agents like chlorine or bromine, and alkylating agents like alkyl halides.
Major Products Formed:
Desmethylthis compound: Formed through reduction.
N-oxide derivative: Formed through oxidation.
Scientific Research Applications
Clomipramine has a wide range of scientific research applications:
Chemistry: Used as a model compound in the study of tricyclic antidepressants.
Biology: Investigated for its effects on neurotransmitter systems and neuronal autophagy.
Industry: Utilized in the development of diagnostic tools and eco-friendly sensors.
Comparison with Similar Compounds
Imipramine: Another tricyclic antidepressant used for similar indications.
Amitriptyline: Known for its sedative properties and used in the treatment of depression and chronic pain.
Nortriptyline: A secondary amine tricyclic antidepressant with a different side effect profile.
Uniqueness of Clomipramine: this compound is unique due to its strong inhibition of serotonin reuptake compared to other tricyclic antidepressants. This makes it particularly effective in treating obsessive-compulsive disorder. Additionally, its metabolite, desmethylthis compound, preferentially inhibits norepinephrine reuptake, providing a dual mechanism of action .
Properties
IUPAC Name |
3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C19H23ClN2/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
GDLIGKIOYRNHDA-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN(C)CCCN1C2=CC=CC=C2CCC3=C1C=C(C=C3)Cl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C19H23ClN2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
17321-77-6 (mono-hydrochloride) |
Source
|
| Record name | Clomipramine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000303491 | |
| 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. | |
DSSTOX Substance ID |
DTXSID6022844 |
Source
|
| Record name | Clomipramine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6022844 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
314.9 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 | Clomipramine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015372 | |
| 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. | |
Boiling Point |
160-170 °C at 3.00E-01 mm Hg, 160-170 °C at 0.3 mm Hg |
Source
|
| Record name | Clomipramine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01242 | |
| 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. | |
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| Record name | Clomipramine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7746 | |
| 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. | |
Solubility |
1.44e-02 g/L |
Source
|
| Record name | Clomipramine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01242 | |
| 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 | Clomipramine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015372 | |
| 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 |
Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α1-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type., The pharmacology of clomipramine is complex and in many ways resembles that of other antidepressants, particularly those agents (eg, selective serotonin-reuptake inhibitors, trazodone) that predominantly potentiate the pharmacologic effects of serotonin (5-HT). Although clomipramine's principal pharmacologic effect in vitro is the selective inhibition of serotonin reuptake, in vivo the drug's pharmacologic activity is not so selective because of the action of its demethylated metabolite, desmethylclomipramine, as an inhibitor of norepinephrine reuptake. As a result of this and other effects, clomipramine also shares the pharmacologic profile of other tricyclic antidepressants., The precise mechanism of action that is responsible for the efficacy of clomipramine in the treatment of obsessive-compulsive disorder is unclear. However, because of its pronounced potency in blocking serotonin reuptake at the presynaptic neuronal membrane and its efficacy in the treatment of obsessive-compulsive disorder, a serotonin hypothesis has been developed to explain the pathogenesis of the condition. The hypothesis postulates that a dysregulation of serotonin is responsible for obsessive-compulsive disorder and that clomipramine is effective because it corrects this imbalance., Clomipramine and its principal metabolite, desmethylclomipramine, have been shown to block the reuptake of serotonin and norepinephrine, respectively, at the presynaptic neuronal membrane. The effects of serotonin and norepinephrine may thus be potentiated. However, it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents. During long-term therapy with most antidepressants (eg, tricyclic antidepressants, monoamine oxidase [MAO] inhibitors), these adaptive changes generally consist of subsensitivity of the noradrenergic adenylate cyclase system in association with a decrease in the number of beta-adrenergic receptors; such effects on noradrenergic receptor function commonly are referred to as "down-regulation." In addition, some antidepressants reportedly decrease the number of 5-HT binding sites following chronic administration., Clomipramine's principal metabolite, desmethylclomipramine, is an inhibitor of norepinephrine reuptake. Clomipramine decreases the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite of norepinephrine, in CSF in patients with obsessive-compulsive disorder. Patients with depressive affective (mood) disorders (e.g., major depressive episode) also exhibit decreases in concentrations of 5-HIAA and MHPG in CSF during treatment with clomipramine. The decrease in the concentration of 5-HIAA in CSF was correlated with inhibition of the in vitro uptake of 3H-serotonin in plasma. The change in concentration of MHPG in CSF during clomipramine therapy was correlated with amelioration of depression., For more Mechanism of Action (Complete) data for Clomipramine (10 total), please visit the HSDB record page. |
Source
|
| Record name | Clomipramine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01242 | |
| 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 | Clomipramine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7746 | |
| 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. | |
Impurities |
N-[3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-t-yl)propyl]-N,N',N'-trimethylpropane-1,3-diamine, 3-(3-chloro-5H-dibenzo[b,f]azepin-5-yl]-N,N-dimethylpropan-1-amine, 3-(3,7-dichloro-10,11-dihydro-5H-dibenzol[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine, 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine, For more Impurities (Complete) data for Clomipramine (11 total), please visit the HSDB record page. |
Source
|
| Record name | Clomipramine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7746 | |
| 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. | |
CAS No. |
303-49-1 |
Source
|
| Record name | Clomipramine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=303-49-1 | |
| 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. | |
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| Record name | Clomipramine [INN:BAN] | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000303491 | |
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| Record name | Clomipramine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01242 | |
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| Record name | clomipramine | |
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| Record name | Clomipramine | |
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| Record name | CLOMIPRAMINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/NUV44L116D | |
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| Record name | Clomipramine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7746 | |
| 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 | Clomipramine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015372 | |
| 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 |
191.5-192, 189.5 °C |
Source
|
| Record name | Clomipramine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01242 | |
| 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 | Clomipramine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015372 | |
| 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. | |
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