Bupropion
Overview
Description
Bupropion, also known by its chemical name 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, is a unique compound primarily used as an antidepressant and smoking cessation aid. It was first developed in 1966 and patented in 1974 by Burroughs Wellcome, later marketed under the brand names Wellbutrin and Zyban . This compound is classified as a norepinephrine-dopamine reuptake inhibitor (NDRI), distinguishing it from other antidepressants that typically target serotonin pathways .
Preparation Methods
Synthetic Routes and Reaction Conditions
The synthesis of bupropion hydrochloride involves several key steps. One common method starts with the bromination of 3’-chloropropiophenone using bromine in the presence of tert-butylamine to form the this compound free base. This is followed by the addition of hydrochloric acid to obtain this compound hydrochloride . Another method involves the bromination of m-chloropropiophenone with sodium bromide and sulfuric acid, followed by amination with tert-butylamine and acidification with hydrogen chloride .
Industrial Production Methods
Industrial production of this compound hydrochloride typically follows similar synthetic routes but is optimized for large-scale manufacturing. The process involves bromination, amination, and acidification steps, with a focus on high yield, low cost, and environmental sustainability. For instance, using polymer-bound pyridinium tribromide instead of liquid bromine can make the process greener and safer .
Chemical Reactions Analysis
Types of Reactions
Bupropion undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized to form hydroxythis compound, a major active metabolite.
Reduction: Reduction reactions can convert this compound to its corresponding alcohol derivatives.
Substitution: Halogen substitution reactions can modify the chlorophenyl group.
Common Reagents and Conditions
Oxidation: Common oxidizing agents include potassium permanganate and chromium trioxide.
Reduction: Reducing agents like lithium aluminum hydride or sodium borohydride are used.
Substitution: Halogenation reagents such as bromine or chlorine in the presence of catalysts.
Major Products Formed
Hydroxythis compound: Formed through oxidation, it is an active metabolite with similar pharmacological effects.
Threohydrothis compound and Erythrohydrothis compound: Formed through reduction reactions.
Scientific Research Applications
Key Applications
-
Major Depressive Disorder (MDD)
- Bupropion is indicated for the treatment of MDD. Clinical trials have shown significant improvements in depression severity, measured by scales such as the Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions (CGI) scores. For instance, a study demonstrated that patients receiving 450 mg/day exhibited notable improvement compared to placebo .
- Seasonal Affective Disorder (SAD)
- Smoking Cessation
- Attention Deficit Hyperactivity Disorder (ADHD)
-
Substance Use Disorders
- This compound has been investigated for its potential role in treating various substance use disorders, including methamphetamine dependence. A study found that this compound reduced subjective drug effects and cravings associated with methamphetamine use, suggesting its utility in addiction treatment .
Case Study 1: this compound in Panic Disorder
A 47-year-old patient diagnosed with panic disorder was treated with this compound over 72 weeks. Initial treatment at 150 mg daily led to significant symptom improvement; however, increased dosage resulted in new panic attacks. This case highlights the need for careful monitoring when adjusting dosages .
Case Study 2: Smoking Cessation
In a clinical trial involving smokers attempting to quit, participants treated with this compound showed a significantly higher cessation rate compared to those on placebo. The study emphasized the effectiveness of this compound as part of a comprehensive smoking cessation program .
Comparative Efficacy Table
Mechanism of Action
Bupropion exerts its effects by inhibiting the reuptake of norepinephrine and dopamine, thereby increasing their levels in the synaptic cleft and prolonging their action . It binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT), preventing the reabsorption of these neurotransmitters into presynaptic neurons . Additionally, this compound acts as a negative allosteric modulator of nicotinic acetylcholine receptors, contributing to its efficacy in smoking cessation .
Comparison with Similar Compounds
Similar Compounds
Duloxetine: A serotonin-norepinephrine reuptake inhibitor (SNRI) used for depression and anxiety.
Venlafaxine: Another SNRI with similar applications.
Methylphenidate: A dopamine-norepinephrine reuptake inhibitor used primarily for attention deficit hyperactivity disorder (ADHD).
Uniqueness of Bupropion
This compound is unique among antidepressants due to its lack of significant serotonergic effects, which reduces the risk of sexual dysfunction and weight gain commonly associated with other antidepressants . Its dual action on norepinephrine and dopamine reuptake makes it particularly effective for patients with hypersomnia and fatigue .
Biological Activity
Bupropion is a unique antidepressant that primarily functions as a norepinephrine-dopamine reuptake inhibitor (NDRI). Its biological activity has been extensively studied, revealing its multifaceted mechanisms of action, therapeutic uses, and effects on various neurochemical systems.
This compound's mechanism of action is complex and not entirely understood. Key findings include:
- Dopaminergic and Noradrenergic Activity : this compound weakly inhibits the reuptake of dopamine and norepinephrine, leading to increased levels of these neurotransmitters in the synaptic cleft. Studies demonstrate that this compound enhances extracellular dopamine levels in the nucleus accumbens, which is associated with reward and motivation pathways .
- Metabolite Influence : The active metabolite hydroxythis compound significantly contributes to this compound's antidepressant effects. It exhibits similar affinity for the norepinephrine transporter (NET) but has about 50% of this compound's antidepressant activity despite higher concentrations in the body .
- Electrophysiological Effects : Acute doses of this compound reduce the firing rates of noradrenergic neurons in the locus ceruleus and dopaminergic neurons in specific brain regions, indicating a selective modulation of neurotransmitter systems .
Clinical Efficacy
This compound is effective in treating various conditions, including major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD), and smoking cessation. Below are summarized findings from clinical studies:
Case Studies
- Panic Disorder Case Report : A patient treated with this compound over 72 weeks showed substantial improvement in panic symptoms and quality of life, with initial titration at 150 mg daily leading to enhanced psychosocial functioning . However, increased dosage resulted in new panic attacks, indicating variability in response based on dosage adjustments.
- Methamphetamine Dependence Study : this compound was found to reduce subjective effects and cravings associated with methamphetamine use, highlighting its potential role in substance use disorders .
Safety and Tolerability
This compound is generally well-tolerated but can cause side effects such as insomnia, dry mouth, and increased anxiety in some patients. Its profile suggests a lower risk of sexual dysfunction compared to selective serotonin reuptake inhibitors (SSRIs), making it a preferred option for certain individuals with depression .
Properties
IUPAC Name |
2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
SNPPWIUOZRMYNY-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C(=O)C1=CC(=CC=C1)Cl)NC(C)(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C13H18ClNO |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7022706 |
Source
|
| Record name | Bupropion | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7022706 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
239.74 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 | Bupropion | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001510 | |
| 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 |
BP: 52 °C at 0.005 mm Hg |
Source
|
| Record name | Bupropion | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6988 | |
| 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 |
Very hygroscopic and susceptible to decomposition, Soluble in methanol, ethanol, acetone, ether, benzene |
Source
|
| Record name | Bupropion | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01156 | |
| 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 | Bupropion | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6988 | |
| 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. | |
Mechanism of Action |
Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with [naltrexone] in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and [naltrexone] increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways., Unicyclic aminoketone with noradrenergic and dopaminergic activity., Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of bupropion. Rats were trained to press one lever when injected i.p. with bupropion (17.0 mg/kg), and another lever when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU 19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic dopamine uptake blocker benztropine produced limited partial substitution. A series of dopamine D1-like and D2-like receptor agonists were also tested: only the D2-like agonist RU 24213 fully substituted; three other D2-like agonists and four D1-like agonists partially substituted (50% < drug responding < 80%). Antagonism of the discriminative effects of bupropion was obtained with a D1- and a D2-like dopamine antagonist. The results demonstrate strong similarities with those obtained using other dopamine uptake inhibitors as training drugs, and support the view that the behavioural effects of bupropion are primarily mediated by dopaminergic mechanisms., The effects of bupropion on core body temperature of intact or reserpinized mice were studied. Intraperitoneal (IP) administration of bupropion to mice induced a dose-dependent hypothermia. The response of bupropion was decreased by the D-2 antagonist sulpiride or pimozide, but not by the D-1 antagonist SCH 23390, antimuscarinic drug atropine, alpha-adrenergic blocker phenoxybenzimine, beta-adrenergic antagonist propranolol or antiserotonergic methergoline. Reserpine induced hypothermia, which was reversed by bupropion administration. The reversal response of bupropion was reduced by propranolol, but not sulpiride, SCH 23390, phenoxybenzamine, atropine or methergoline. It is concluded that bupropion-induced hypothermia may be mediated through D-2 receptor activation, while the reversal of reserpine-induced hypothermia by bupropion may be exerted through beta-adrenergic stimulation., Bupropion (12.5-75 mg kg-1) was given intraperitoneally to rats and was found to decrease the food consumption of the animals dose-dependently. While phenoxybenzamine, propranolol and methergoline failed to antagonize the anorectic effect of the drug; pimozide a dopamine receptor blocker decreased anorexia induced by bupropion. Bupropion (12.5-50 mg kg-1) also caused a marked increase in locomotor activity of the rats. The increase in locomotion produced by bupropion was completely antagonized by pretreatment of the animals with pimozide and reserpine plus a-methyl-p-tyrosine, but not by pretreatment with phenoxybenzamine, propranolol or methergoline. Taking into considerations the evidences of dopaminergic properties of bupropion shown by the others, it could be suggested that the anorexia and hyperactivity produced by bupropion may be induced through the indirect dopaminergic mechanism., For more Mechanism of Action (Complete) data for Bupropion (7 total), please visit the HSDB record page. |
Source
|
| Record name | Bupropion | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01156 | |
| 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 | Bupropion | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6988 | |
| 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 |
Pale yellow oil | |
CAS No. |
34911-55-2, 144445-76-1, 144445-75-0, 34841-39-9 |
Source
|
| Record name | (±)-Bupropion | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=34911-55-2 | |
| 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 | (-)-Bupropion | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=144445-76-1 | |
| 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. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | (+)-Bupropion | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=144445-75-0 | |
| 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 | Bupropion [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0034911552 | |
| 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 | Bupropion | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01156 | |
| 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 | Bupropion | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7022706 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | BUPROPION | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/01ZG3TPX31 | |
| 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 | Bupropion | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/6988 | |
| 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 | Bupropion | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001510 | |
| 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 |
233-234 °C |
Source
|
| Record name | Bupropion | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01156 | |
| 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) | |
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Retrosynthesis Analysis
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