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Record Information
Version2.0
Creation Date2009-07-21 20:28:23 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2986
Identification
Common NameSibutramine
ClassSmall Molecule
DescriptionSibutramine (trade name Meridia in the USA, Reductil in Europe and other countries), usually as sibutramide hydrochloride monohydrate, is an orally administered agent for the treatment of obesity. It is a centrally acting stimulant chemically related to amphetamines. Sibutramine is classified as a Schedule IV controlled substance in the United States. In October 2010, Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the drug increases the risk of heart attack and stroke in patients with a history of heart disease.
Compound Type
  • Amine
  • Anorexigenic Agent
  • Antidepressant
  • Antidepressive Agent
  • Appetite Depressant
  • Drug
  • Metabolite
  • Organic Compound
  • Organochloride
  • Stimulant
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Butramin
Medaria
Meridia
Reductil
Sibutramina
Sibutraminum
Chemical FormulaC17H26ClN
Average Molecular Mass279.848 g/mol
Monoisotopic Mass279.175 g/mol
CAS Registry Number106650-56-0
IUPAC Name{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}dimethylamine
Traditional Namesibutramine
SMILESCC(C)CC(N(C)C)C1(CCC1)C1=CC=C(Cl)C=C1
InChI IdentifierInChI=1/C17H26ClN/c1-13(2)12-16(19(3)4)17(10-5-11-17)14-6-8-15(18)9-7-14/h6-9,13,16H,5,10-12H2,1-4H3
InChI KeyInChIKey=UNAANXDKBXWMLN-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as chlorobenzenes. Chlorobenzenes are compounds containing one or more chlorine atoms attached to a benzene moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassHalobenzenes
Direct ParentChlorobenzenes
Alternative Parents
Substituents
  • Aralkylamine
  • Chlorobenzene
  • Aryl halide
  • Aryl chloride
  • Tertiary aliphatic amine
  • Tertiary amine
  • Organic nitrogen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point191-192°C
Boiling PointNot Available
Solubility2.9 mg/mL (in pH 5.2 water)
LogP5.2
Predicted Properties
PropertyValueSource
Water Solubility0.00094 g/LALOGPS
logP5.05ALOGPS
logP5.2ChemAxon
logS-5.5ALOGPS
pKa (Strongest Basic)9.77ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area3.24 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity83.92 m³·mol⁻¹ChemAxon
Polarizability32.9 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-07bf-9640000000-63dab33ab67c598b8779JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-003r-1930000000-b90a7add9041c09efb5eJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-005i-1930000000-524395362f2824760185JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 35V, Positivesplash10-004r-1900000000-f5b2dc8eb6cd3b695581JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0090000000-5389ad6755b0b9d3f3b9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-05gr-2290000000-2c27a844d317defb5527JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-9540000000-8a05a19349a6eb1a0852JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0090000000-4ddcf8011b3e19977025JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0190000000-3b0d542f8a73ec923a94JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-03k9-4980000000-3be05aa6c152cc4a87a8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0190000000-f6b1e08de10b5f29753dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0190000000-d2de1be3a5b498179198JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01q9-9700000000-4feca2b9a2fe44fb0adcJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-001i-0590000000-e841763a4ecec6c31d60JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-2940000000-780b7e85e0bd0df044daJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014i-3900000000-80359ff0e43a20860a42JSpectraViewer
Toxicity Profile
Route of ExposureRapid absorption following oral administration. Absolute bioavailability is not known, but at least 77% of a single oral dose of sibutramine is absorbed.
Mechanism of ToxicitySibutramine produces its therapeutic effects by inhibition of norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and to a lesser extent, dopamine reuptake at the neuronal synapse. By inhibiting the reuptake of these neurotransmitters, sibutramine promotes a sense of satiety and decrease in appetite, thereby reducing food intake. Data from animal studies also suggest that sibutramine may also increase energy expenditure through thermogenic effects in both the basal and fed states, but this has not been confirmed in humans. Sibutramine and its major pharmacologically active metabolites (M1 and M2) do not act via release of monoamines.
MetabolismHepatic Route of Elimination: Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6. Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. The primary route of excretion for M1 and M2 is hepatic metabolism and for M5 and M6 is renal excretion. Half Life: 1.1 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of obesity.
Minimum Risk LevelNot Available
Health EffectsUsing large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.
SymptomsSide effects include dry mouth, anorexia, insomnia, constipation and headache.
TreatmentTreatment should consist of general measures employed in the management of overdosage: an airway should be established as needed; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of p-blockers may be indicated to control elevated blood pressure or tachycardia. (6)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01105
HMDB IDHMDB15237
PubChem Compound ID5210
ChEMBL IDCHEMBL1419
ChemSpider ID5021
KEGG IDC07247
UniProt IDNot Available
OMIM ID
ChEBI ID458192
BioCyc IDNot Available
CTD IDNot Available
Stitch IDSibutramine
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkSibutramine
References
Synthesis Reference

Chris Senanayake, “Methods of preparing didesmethylsibutramine and other sibutramine derivatives.” U.S. Patent US20020183554, issued December 05, 2002.

MSDST3D2986.pdf
General References
  1. Sharma B, Henderson DC: Sibutramine: current status as an anti-obesity drug and its future perspectives. Expert Opin Pharmacother. 2008 Aug;9(12):2161-73. doi: 10.1517/14656566.9.12.2161 . [18671470 ]
  2. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. [19475780 ]
  3. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC: Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord. 1998 Aug;22 Suppl 1:S18-28; discussion S29. [9758240 ]
  4. Stock MJ: Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes Relat Metab Disord. 1997 Mar;21 Suppl 1:S25-9. [9130038 ]
  5. Drugs.com [Link]
  6. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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
References
  1. Tziomalos K, Krassas GE, Tzotzas T: The use of sibutramine in the management of obesity and related disorders: an update. Vasc Health Risk Manag. 2009;5(1):441-52. [19475780 ]
  2. Gomis Barbara R: [Pharmacological treatment of obesity]. Rev Med Univ Navarra. 2004 Apr-Jun;48(2):63-5. [15382615 ]
  3. Berke EM, Morden NE: Medical management of obesity. Am Fam Physician. 2000 Jul 15;62(2):419-26. [10929704 ]
  4. Nakagawa T, Ukai K, Ohyama T, Gomita Y, Okamura H: Effects of sibutramine on the central dopaminergic system in rodents. Neurotox Res. 2001 Jul;3(3):235-47. [15111248 ]
  5. Krahn LE, Moore WR, Altchuler SI: Narcolepsy and obesity: remission of severe cataplexy with sibutramine. Sleep Med. 2001 Jan;2(1):63-65. [11152984 ]
  6. Balcioglu A, Wurtman RJ: Sibutramine, a serotonin uptake inhibitor, increases dopamine concentrations in rat striatal and hypothalamic extracellular fluid. Neuropharmacology. 2000 Sep;39(12):2352-9. [10974319 ]
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
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Heusser K, Engeli S, Tank J, Diedrich A, Wiesner S, Janke J, Luft FC, Jordan J: Sympathetic vasomotor tone determines blood pressure response to long-term sibutramine treatment. J Clin Endocrinol Metab. 2007 Apr;92(4):1560-3. Epub 2007 Feb 6. [17284621 ]
  3. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H, Sharma AM: Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes (Lond). 2005 May;29(5):509-16. [15685250 ]
  4. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Kruger N, Strauss A, Stoffels G, Luft FC, Jordan J: Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther. 2006 May;79(5):500-8. [16678551 ]
  5. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002 Nov 5;106(19):2459-65. [12417543 ]
  6. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J: Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients--sibutramine and blood pressure. Clin Auton Res. 2005 Jun;15(3):200-6. [15944869 ]
General Function:
Virus receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 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 phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.(Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
Gene Name:
HTR2A
Uniprot ID:
P28223
Molecular Weight:
52602.58 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 84742
References
  1. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
General Function:
Serotonin receptor activity
Specific Function:
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives 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. 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. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5-hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine.
Gene Name:
HTR2B
Uniprot ID:
P41595
Molecular Weight:
54297.41 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 84742
References
  1. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
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
TypeValueAssay TypeAssay Source
Inhibitory>10 uMNot AvailableBindingDB 84742
References
  1. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M: Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23. Epub 2004 Jul 30. [15322733 ]
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
References
  1. Vazquez Roque MI, Camilleri M, Clark MM, Tepoel DA, Jensen MD, Graszer KM, Kalsy SA, Burton DD, Baxter KL, Zinsmeister AR: Alteration of gastric functions and candidate genes associated with weight reduction in response to sibutramine. Clin Gastroenterol Hepatol. 2007 Jul;5(7):829-37. Epub 2007 Jun 4. [17544870 ]