T3DB: Bupropion

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (14)XML

Targets (14)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:29 UTC

Update Date

2014-12-24 20:25:55 UTC

Accession Number

T3D2999

Identification

Common Name

Bupropion

Class

Small Molecule

Description

Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. The antidepressant effect of bupropion is considered to be mediated by its dopaminergic and noradrenergic action. Bupropion has also been shown to act as a competitive alpha-3-beta-4- nicotinic antagonist, the alpha-3-beta-4-antagonism has been shown to interrupt addiction in studies of other drugs such as ibogaine. This alpha-3-beta-4-antagonism correlates quite well with the observed effect of interrupting addiction. A unicyclic, aminoketone antidepressant. The mechanism of its therapeutic actions is not well understood, but it does appear to block dopamine uptake. The hydrochloride is available as an aid to smoking cessation treatment; Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO. The antidepressant effect of bupropion is considered to be mediated by its dopaminergic and noradrenergic action. Bupropion has also been shown to act as a competitive alpha-3-beta-4-nicotinic antagonist, the alpha-3-beta-4-antagonism has been shown to interrupt addiction in studies of other drugs such as ibogaine. This alpha-3-beta-4-antagonism correlates quite well with the observed effect of interrupting addiction. Bupropion (amfebutamone) (brand names Wellbutrin and Zyban) is an antidepressant of the aminoketone class, chemically unrelated to tricyclics or selective serotonin reuptake inhibitors (SSRIs). It is similar in structure to the stimulant cathinone, and to phenethylamines in general. It is a chemical derivative of diethylpropion, an amphetamine-like substance used as an anorectic. Bupropion is both a dopamine reuptake inhibitor and a norepinephrine reuptake inhibitor. It is often used as a smoking cessation aid.

Compound Type

Amine
Antidepressant
Antidepressant, Second-Generation
Antidepressive Agent, Second-Generation
Dopamine Uptake Inhibitor
Drug
Ester
Food Toxin
Metabolite
Organic Compound
Organochloride
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
(+-)-Bupropion
Amfebutamona
Amfebutamone
Amfebutamonum
Aplenzin
Budeprion
BUPROBAN
Elontril
Forfivo
Prexaton
Voxra
Wellbatrin
Wellbutrin
Wellbutrin SR
Wellbutrin XL
Zyban

Chemical Formula

C₁₃H₁₈ClNO

Average Molecular Mass

239.741 g/mol

Monoisotopic Mass

239.108 g/mol

CAS Registry Number

34841-39-9

IUPAC Name

2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one

Traditional Name

bupropion

SMILES

CC(NC(C)(C)C)C(=O)C1=CC(Cl)=CC=C1

InChI Identifier

InChI=1/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3

InChI Key

InChIKey=SNPPWIUOZRMYNY-UHFFFAOYNA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as alkyl-phenylketones. These are aromatic compounds containing a ketone substituted by one alkyl group, and a phenyl group.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbonyl compounds

Direct Parent

Alkyl-phenylketones

Alternative Parents

Substituents

Alkyl-phenylketone
Phenylpropane
Benzoyl
Aryl alkyl ketone
Chlorobenzene
Halobenzene
Aryl chloride
Aryl halide
Monocyclic benzene moiety
Benzenoid
Alpha-aminoketone
Secondary aliphatic amine
Secondary amine
Organochloride
Organohalogen compound
Organic oxide
Organopnictogen compound
Organic nitrogen compound
Amine
Organonitrogen compound
Hydrocarbon derivative
Aromatic homomonocyclic compound

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

secondary amino compound (CHEBI:3219 )
monochlorobenzenes (CHEBI:3219 )
propanone (CHEBI:3219 )
aromatic ketone (CHEBI:3219 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Brain
Liver

Pathways

Not Available

Applications

antidepressant

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	233-234°C
Boiling Point	Not Available
Solubility	312 mg/ml
LogP	3.6

Predicted Properties

Property	Value	Source
Water Solubility	0.069 g/L	ALOGPS
logP	3.28	ALOGPS
logP	3.27	ChemAxon
logS	-3.5	ALOGPS
pKa (Strongest Acidic)	18.29	ChemAxon
pKa (Strongest Basic)	8.22	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	29.1 Å²	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	67.7 m³·mol⁻¹	ChemAxon
Polarizability	25.93 Å³	ChemAxon
Number of Rings	1	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-000l-5900000000-1b5fb2e947791614a61d	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-001i-0910000000-fa2592b7296c7561333c	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-c10af1c8e3619fe0bffc	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0490000000-55448af4d9a8ce866a88	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-2883ba18321a8b8228a1	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0159-0900000000-7d6cad849706146ddab3	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0159-0900000000-0fca8999746b69ee4fc1	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-b64f8d2b50bede574f63	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-2edefa63d5f6f1b08db7	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0006-0490000000-b8ea1de058a84547700d	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0910000000-6f471b9150fb1b7f6fcc	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-0159-0900000000-cc966137ee3283828af7	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-00lr-0900000000-7f86f38f740aa41b244b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-e7f2cfdbabbd35a9b643	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-4daf0e10db1e5f2750bf	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , positive	splash10-001i-0900000000-f77a450be176593153d2	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-00m0-0910000000-d2eb7265b058766459c9	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-001i-0910000000-fa2592b7296c7561333c	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-001i-0900000000-4d831e97d7e7dfff141b	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 60V, Positive	splash10-00lr-0900000000-65c6a707c92719eb037b	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0006-0290000000-f40e79f27fd0f3448f9a	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-000x-2950000000-e144eddb8d64cdf24711	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0596-9500000000-9c44a89baee334f5ce9c	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-000i-0090000000-f90eefcb5d4049067bbd	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-000i-2490000000-afd91ae0bad53e4c5c9f	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-02mi-6930000000-94751c5f94b6dd91d63e	2016-08-03	View Spectrum

Toxicity Profile

Route of Exposure

For sustained release, peak plasma concentrations are achieved within 3 hours.

Mechanism of Toxicity

Bupropion selectively inhibits the neuronal reuptake of dopamine, norepinephrine, and serotonin; actions on dopaminergic systems are more significant than imipramine or amitriptyline whereas the blockade of norepinephrine and serotonin reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. The increase in norepinephrine may attenuate nicotine withdrawal symptoms and the increase in dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Bupropion exhibits moderate anticholinergic effects.

Metabolism

Reduction of the carbonyl groupand/or hydroxylation of the tert-butyl group of bupropion. Route of Elimination: Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. Half Life: 24 hours

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the treatment of depression and as aid to smoking cessation.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest.

Treatment

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known. Due to the dose-related risk of seizures with Bupropion, hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate. (12)

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

3219

BioCyc ID

CPD-3481

CTD ID

Not Available

Stitch ID

Bupropion

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Bupropion

References

Synthesis Reference

DrugSyn.org

MSDS

Link

General References

Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA: A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability. J Clin Psychopharmacol. 2006 Oct;26(5):482-8. [16974189 ]
Fryer JD, Lukas RJ: Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther. 1999 Jan;288(1):88-92. [9862757 ]
Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA: 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7(3):106-13. [16027765 ]
Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, VanMeter S, Harriett AE, Wang Y: Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry. 2005 Aug;66(8):974-81. [16086611 ]
Annual report on the results of treatment in gynecological cancer. Twenty-first volume. Statements of results obtained in patients treated in 1982 to 1986, inclusive 3 and 5-year survival up to 1990. Int J Gynaecol Obstet. 1991 Sep;36 Suppl:1-315. [1684162 ]
Mooney ME, Sofuoglu M: Bupropion for the treatment of nicotine withdrawal and craving. Expert Rev Neurother. 2006 Jul;6(7):965-81. [16831112 ]
Hesse LM, Sakai Y, Vishnuvardhan D, Li AP, von Moltke LL, Greenblatt DJ: Effect of bupropion on CYP2B6 and CYP3A4 catalytic activity, immunoreactive protein and mRNA levels in primary human hepatocytes: comparison with rifampicin. J Pharm Pharmacol. 2003 Sep;55(9):1229-39. [14604466 ]
Goodnick PJ: Pharmacokinetic optimisation of therapy with newer antidepressants. Clin Pharmacokinet. 1994 Oct;27(4):307-30. [7834966 ]
Inoue T, Kitaichi Y, Koyama T: [Treatment strategy of refractory depression and its presynaptic mechanism of action]. Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 Feb;23(1):11-20. [12690637 ]
Hu KQ, Tiyyagura L, Kanel G, Redeker AG: Acute hepatitis induced by bupropion. Dig Dis Sci. 2000 Sep;45(9):1872-3. [11052334 ]
Drugs.com [Link]
RxList: The Internet Drug Index (2009). [Link]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Not Available

Targets

Target Details

1. Sodium-dependent dopamine transporter

General Function:: Monoamine transmembrane transporter activity
Specific Function:: Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:: SLC6A3
Uniprot ID:: Q01959
Molecular Weight:: 68494.255 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	0.441 uM	Not Available	BindingDB 50048392
Inhibitory	0.52 uM	Not Available	BindingDB 50048392
Inhibitory	0.562 uM	Not Available	BindingDB 50048392
Inhibitory	0.784 uM	Not Available	BindingDB 50048392
Inhibitory	0.871 uM	Not Available	BindingDB 50048392
IC50	0.658 uM	Not Available	BindingDB 50048392
IC50	0.66 uM	Not Available	BindingDB 50048392
IC50	0.945 uM	Not Available	BindingDB 50048392
IC50	1.567 uM	Not Available	BindingDB 50048392
IC50	2.9 uM	Not Available	BindingDB 50048392

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Miller DK, Sumithran SP, Dwoskin LP: Bupropion inhibits nicotine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine. J Pharmacol Exp Ther. 2002 Sep;302(3):1113-22. [12183670 ]
Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S: Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl). 2002 Aug;163(1):102-5. Epub 2002 Jul 13. [12185406 ]
Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison RT, Baldwin RM, Seibyl JP, Innis RB: Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration. Neuropsychopharmacology. 2003 Feb;28(2):413-20. Epub 2002 Jul 19. [12589396 ]
Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B: In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry. 2003 Oct 15;54(8):800-5. [14550679 ]
Szabo Z, Argyelan M, Kanyo B, Pavics L, Janka Z: [Change of dopamine transporter activity (DAT) during the action of bupropion (in depression)]. Neuropsychopharmacol Hung. 2004 Jun;6(2):79-81. [15787205 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation. J Med Chem. 2010 Mar 11;53(5):2204-14. doi: 10.1021/jm9017465. [20158204 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes. J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8. [21058665 ]
Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI: Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232. [20509659 ]
Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction. J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z. [19821577 ]
Lapinsky DJ, Aggarwal S, Huang Y, Surratt CK, Lever JR, Foster JD, Vaughan RA: A novel photoaffinity ligand for the dopamine transporter based on pyrovalerone. Bioorg Med Chem. 2009 Jun 1;17(11):3770-4. doi: 10.1016/j.bmc.2009.04.057. Epub 2009 May 3. [19442525 ]
Carroll FI: 2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy. J Med Chem. 2003 May 8;46(10):1775-94. [12723940 ]
Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW: Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711. [12431845 ]
Pristupa ZB, Wilson JM, Hoffman BJ, Kish SJ, Niznik HB: Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding. Mol Pharmacol. 1994 Jan;45(1):125-35. [8302271 ]

Target Details

2. Sodium-dependent noradrenaline transporter

General Function:: Norepinephrine:sodium symporter activity
Specific Function:: Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name:: SLC6A2
Uniprot ID:: P23975
Molecular Weight:: 69331.42 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	6.97 uM	Not Available	BindingDB 50048392
Inhibitory	>10 uM	Not Available	BindingDB 50048392
IC50	0.443 uM	Not Available	BindingDB 50048392
IC50	1.45 uM	Not Available	BindingDB 50048392
IC50	1.85 uM	Not Available	BindingDB 50048392

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
Mitchell HA, Ahern TH, Liles LC, Javors MA, Weinshenker D: The effects of norepinephrine transporter inactivation on locomotor activity in mice. Biol Psychiatry. 2006 Nov 15;60(10):1046-52. Epub 2006 Aug 7. [16893531 ]
Bondarev ML, Bondareva TS, Young R, Glennon RA: Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol. 2003 Aug 1;474(1):85-93. [12909199 ]
Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction. J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z. [19821577 ]
Carroll FI: 2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy. J Med Chem. 2003 May 8;46(10):1775-94. [12723940 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation. J Med Chem. 2010 Mar 11;53(5):2204-14. doi: 10.1021/jm9017465. [20158204 ]
Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI: Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232. [20509659 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes. J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8. [21058665 ]
Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW: Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711. [12431845 ]

Target Details

3. Sodium-dependent serotonin transporter

General Function:: Serotonin:sodium symporter activity
Specific Function:: Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
Gene Name:: SLC6A4
Uniprot ID:: P31645
Molecular Weight:: 70324.165 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	9.1 uM	Not Available	BindingDB 50048392
Inhibitory	>10 uM	Not Available	BindingDB 50048392
IC50	47 uM	Not Available	BindingDB 50048392
IC50	>0.1 uM	Not Available	BindingDB 50048392
IC50	>100 uM	Not Available	BindingDB 50048392

References

Carroll FI: 2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy. J Med Chem. 2003 May 8;46(10):1775-94. [12723940 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation. J Med Chem. 2010 Mar 11;53(5):2204-14. doi: 10.1021/jm9017465. [20158204 ]
Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI: Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232. [20509659 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes. J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8. [21058665 ]
Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [9537821 ]
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW: Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711. [12431845 ]
Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction. J Med Chem. 2009 Nov 12;52(21):6768-81. doi: 10.1021/jm901189z. [19821577 ]

Target Details

4. Neuronal acetylcholine receptor subunit alpha-3

General Function:: Ligand-gated ion channel activity
Specific Function:: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name:: CHRNA3
Uniprot ID:: P32297
Molecular Weight:: 57479.54 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	1 uM	Not Available	BindingDB 50048392
IC50	1.8 uM	Not Available	BindingDB 50048392

References

Fryer JD, Lukas RJ: Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther. 1999 Jan;288(1):88-92. [9862757 ]
Slemmer JE, Martin BR, Damaj MI: Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 2000 Oct;295(1):321-7. [10991997 ]
Jensen AA, Frolund B, Liljefors T, Krogsgaard-Larsen P: Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45. [16033252 ]
Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI: Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232. [20509659 ]

Target Details

5. Neuronal acetylcholine receptor subunit alpha-4

General Function:: Ligand-gated ion channel activity
Specific Function:: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodium ions.
Gene Name:: CHRNA4
Uniprot ID:: P43681
Molecular Weight:: 69956.47 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	0.012 uM	Not Available	BindingDB 50048392
IC50	12 uM	Not Available	BindingDB 50048392

References

Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation. J Med Chem. 2010 Mar 11;53(5):2204-14. doi: 10.1021/jm9017465. [20158204 ]
Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI: Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48. doi: 10.1021/jm1003232. [20509659 ]
Carroll FI, Blough BE, Mascarella SW, Navarro HA, Eaton JB, Lukas RJ, Damaj MI: Nicotinic acetylcholine receptor efficacy and pharmacological properties of 3-(substituted phenyl)-2beta-substituted tropanes. J Med Chem. 2010 Dec 9;53(23):8345-53. doi: 10.1021/jm100994w. Epub 2010 Nov 8. [21058665 ]

Target Details

6. Muscarinic acetylcholine receptor M2

General Function:: G-protein coupled acetylcholine receptor activity
Specific Function:: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol.
Gene Name:: CHRM2
Uniprot ID:: P08172
Molecular Weight:: 51714.605 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]
Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]

Target Details

7. 5-hydroxytryptamine receptor 1A

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
Gene Name:: HTR1A
Uniprot ID:: P08908
Molecular Weight:: 46106.335 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

8. 5-hydroxytryptamine receptor 2C

General Function:: Serotonin receptor activity
Specific Function:: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
Gene Name:: HTR2C
Uniprot ID:: P28335
Molecular Weight:: 51820.705 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

9. Alpha-2A adrenergic receptor

General Function:: Thioesterase binding
Specific Function:: Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.
Gene Name:: ADRA2A
Uniprot ID:: P08913
Molecular Weight:: 48956.275 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

10. Histamine H1 receptor

General Function:: Histamine receptor activity
Specific Function:: In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Gene Name:: HRH1
Uniprot ID:: P35367
Molecular Weight:: 55783.61 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [7855217 ]

Target Details

11. Muscarinic acetylcholine receptor M1

General Function:: Phosphatidylinositol phospholipase c activity
Specific Function:: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:: CHRM1
Uniprot ID:: P11229
Molecular Weight:: 51420.375 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]

Target Details

12. Muscarinic acetylcholine receptor M3

General Function:: Receptor activity
Specific Function:: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:: CHRM3
Uniprot ID:: P20309
Molecular Weight:: 66127.445 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]

Target Details

13. Muscarinic acetylcholine receptor M4

General Function:: Guanyl-nucleotide exchange factor activity
Specific Function:: The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase.
Gene Name:: CHRM4
Uniprot ID:: P08173
Molecular Weight:: 53048.65 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	>10 uM	Not Available	BindingDB 50048392

References

Stanton T, Bolden-Watson C, Cusack B, Richelson E: Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol. 1993 Jun 9;45(11):2352-4. [8100134 ]

Target Details

14. Neuronal acetylcholine receptor subunit alpha-7

General Function:: Toxic substance binding
Specific Function:: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is blocked by alpha-bungarotoxin.
Gene Name:: CHRNA7
Uniprot ID:: P36544
Molecular Weight:: 56448.925 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	50 uM	Not Available	BindingDB 50048392

References

Jensen AA, Frolund B, Liljefors T, Krogsgaard-Larsen P: Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45. [16033252 ]

Bupropion (T3D2999)

Structure for T3D2999: Bupropion

Targets

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