Bupropion
Description
Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI) and a nicotinic acetylcholine receptor antagonist. It is structurally distinct from other antidepressants, belonging to the aminoketone class. Its primary mechanism involves inhibiting the reuptake of dopamine (DA) and norepinephrine (NE), with minimal effect on serotonin (5-HT) systems . The drug is metabolized primarily by CYP2B6 into active metabolites, including hydroxythis compound, which contributes significantly to its therapeutic effects .
This compound is indicated for major depressive disorder (MDD) and smoking cessation. Its sustained-release (SR) formulation, approved in 1996, offers comparable efficacy to the immediate-release (IR) version but with a reduced seizure risk (0.1% vs. 0.4% for IR) and fewer side effects, such as insomnia and agitation . Unlike selective serotonin reuptake inhibitors (SSRIs), this compound lacks significant sexual side effects, making it preferable for patients with such concerns .
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. | |
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) | |
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
Synthetic Reactions
Bupropion hydrochloride is synthesized via a two-step bromination-amination sequence followed by salt formation:
Step 1: Bromination of 3'-Chloropropiophenone
Bromine reacts with 3'-chloropropiophenone (C₉H₇ClO) to form 2-bromo-1-(3-chlorophenyl)propan-1-one. This α-bromination proceeds in dichloromethane (DCM) or water with stoichiometric bromine (Br₂) at 20–35°C. Over-bromination can occur, yielding 2,2-dibromo byproducts if excess Br₂ is used.
Reaction Conditions:
| Parameter | Value |
|---|---|
| Solvent | DCM, water, or ethyl acetate |
| Temperature | 20–35°C |
| Bromine equivalents | 1.1–1.2 eq |
| Yield (monobromo) | 75–86% |
Step 2: Nucleophilic Amination
The bromoketone intermediate reacts with tert-butylamine (C₄H₁₁N) in acetonitrile (ACN) or N-methyl-2-pyrrolidone (NMP) at 60–95°C. This SN2 displacement replaces the bromine with a tert-butylamino group, forming this compound free base.
Key Findings:
-
NMP accelerates the reaction rate (3–6 hours vs. 24 hours in ACN).
-
Excess tert-butylamine (3–5 eq) ensures complete conversion.
-
Decomposition occurs above 95°C or in polar aprotic solvents like DMSO.
Solvent Screening Results :
| Solvent System | tert-BuNH₄Br Precipitate? | Yield (%) |
|---|---|---|
| ACN | Yes | 86 |
| 50% ACN:DCM | No | 24 |
| 75% ACN:DCM | Minimal | 76 |
Step 3: Hydrochloride Salt Formation
This compound free base is treated with HCl in isopropanol (IPA) at 0–10°C to precipitate this compound hydrochloride. Purification via recrystallization in methanol/IPA achieves ≥99.9% purity.
Optimized Conditions :
-
IPA-HCl addition until pH 2.
-
Drying under vacuum at 70–75°C reduces residual solvents (LOD <0.5%).
Modifications :
-
Bromine → N-Bromosuccinimide (NBS): Reduces toxicity and dibromination byproducts.
-
NMP → Cyrene (dihydrolevoglucosenone): A biobased solvent with lower reprotoxicity.
-
DCM → Ethyl Acetate: Safer extraction solvent.
Waste Reduction Metrics :
| Metric | Traditional Process | Greener Process |
|---|---|---|
| Process Mass Intensity | 138 kg kg⁻¹ | 46 kg kg⁻¹ |
| E-Factor | 137 | 45 |
Primary Metabolites:
-
Hydroxythis compound (C₁₃H₁₈ClNO₂): Formed via CYP2B6-mediated hydroxylation of the tert-butyl group.
-
Threo-/Erythro-Hydrothis compound: Reduction of the ketone group by non-CYP enzymes.
Metabolite Pharmacokinetics :
| Metabolite | Plasma Concentration (vs. This compound) | NET Affinity (vs. This compound) |
|---|---|---|
| Hydroxythis compound | 10× higher | 100% |
| Threohydrothis compound | Comparable | 20% |
Degradation and Stability
This compound decomposes under thermal or acidic conditions:
-
Thermal Degradation: At >95°C, the free base undergoes retro-aldol cleavage, yielding 3-chlorobenzoic acid and tert-butylamine derivatives.
-
Acidic Hydrolysis: Protonation of the ketone group leads to ring-substituted byproducts.
Stability Data :
| Condition | Decomposition Products | Half-Life |
|---|---|---|
| Neat, 25°C | Unidentified polar compounds | 48 hours |
| 1 M HCl, 60°C | 3-Chlorobenzoic acid | 2 hours |
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
Pharmacokinetic and Pharmacodynamic Differences
Biological Activity
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.
Q & A
Basic Research Questions
Q. What is the primary neuropharmacological mechanism of bupropion's antidepressant effect, and what methodologies are used to validate this mechanism?
this compound primarily acts as a dual norepinephrine (NE) and dopamine (DA) reuptake inhibitor, with negligible serotonergic activity. This mechanism is validated using in vivo microdialysis to measure extracellular NE/DA levels in rodent brains and behavioral assays such as the forced swim test (FST) to assess antidepressant efficacy. Receptor binding assays confirm its lack of affinity for serotonin transporters or postsynaptic receptors, distinguishing it from SSRIs .
Q. How do preclinical models differentiate this compound's antidepressant effects from its stimulant properties?
Preclinical studies employ behavioral despair tests (e.g., FST) to quantify antidepressant activity and locomotor activity assays to evaluate stimulant effects. For example, this compound reduces immobility in FST (antidepressant effect) but increases locomotor activity at higher doses. Metabolites like BW 306 show greater selectivity for antidepressant effects, as demonstrated in reserpine antagonism assays, while this compound itself exhibits mixed stimulant activity .
Q. What experimental designs are used to assess this compound's efficacy in smoking cessation, and how do researchers control for cognitive bias?
Randomized controlled trials (RCTs) compare this compound with placebo or nicotine replacement therapy (NRT), using abstinence rates as primary endpoints. Cognitive outcomes (e.g., working memory) are measured via standardized neuropsychological tests. Selection bias is mitigated by excluding subjects unable to abstain overnight, though this may limit generalizability. Blinded protocols and crossover designs reduce observer bias .
Advanced Research Questions
Q. What experimental approaches are used to investigate this compound's inhibition of heteromeric 5-HT3AB receptors, and how do these findings impact therapeutic understanding?
Voltage-clamp electrophysiology in Xenopus oocytes expressing 5-HT3AB receptors demonstrates dose-dependent, non-competitive inhibition by this compound and hydroxythis compound at clinically relevant concentrations (IC₅₀ ≈ 10–20 μM). Pre-incubation protocols confirm non-use dependence. These findings suggest this compound's serotonergic modulation extends beyond DA/NE reuptake, potentially explaining its efficacy in comorbid depression and substance use disorders .
Q. How do genetic polymorphisms in CYP2B6 influence this compound pharmacokinetics, and what methodologies quantify these variations?
Genotyping via PCR-RFLP identifies CYP2B6 alleles (e.g., *4, *6) linked to altered enzyme activity. Population pharmacokinetic modeling reveals *4 carriers exhibit 1.66-fold higher this compound clearance. HPLC quantifies plasma concentrations of this compound and hydroxythis compound, showing *1/*4 genotypes have higher metabolite Cmax. These methods highlight pharmacogenomic variability in therapeutic response and toxicity risk .
Q. What methodological challenges arise in characterizing this compound's stereoselective metabolism, and how do enantiomer-specific assays address these?
this compound rapidly racemizes in vivo, complicating enantiomer-specific analysis. Chiral chromatography (e.g., LC-MS with β-cyclodextrin columns) distinguishes (R)- and (S)-bupropion. Human liver microsomes reveal CYP2B6 preferentially metabolizes (S)-bupropion to (R,R)-hydroxythis compound. Isotope-labeled tracers and stereospecific inhibitors (e.g., selegiline) further elucidate enantiomer contributions to clinical effects .
Q. How do contradictory findings on this compound's active moieties (parent drug vs. metabolites) inform experimental design in depression research?
Discrepancies arise from metabolite-specific activity: BW 306 (a metabolite) shows greater antidepressant potency in rodent models, while this compound itself drives stimulant effects. Parallel quantification of parent drug and metabolites via LC-MS in plasma/brain tissue clarifies their contributions. In vitro CYP2B6 inhibition assays (e.g., using selegiline) isolate metabolite formation pathways .
Q. Methodological Considerations for Data Contradictions
- Receptor Binding vs. Behavioral Data : While this compound lacks direct serotonergic receptor affinity , its inhibition of 5-HT3AB receptors suggests indirect modulation. Researchers reconcile this by combining in vitro receptor assays with in vivo microdialysis measuring 5-HT levels.
- Metabolite Activity : Conflicting reports on metabolite efficacy (e.g., BW 306 vs. This compound) are addressed using selective CYP2B6 inhibitors to block metabolite formation during behavioral testing .
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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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
