Tmic
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Record Information
Version2.0
Creation Date2009-07-05 02:43:46 UTC
Update Date2014-12-24 20:25:41 UTC
Accession NumberT3D2554
Identification
Common NameBaclofen
ClassSmall Molecule
DescriptionBaclofen is a gamma-amino-butyric acid (GABA) derivative used as a skeletal muscle relaxant. Baclofen stimulates GABA-B receptors leading to decreased frequency and amplitude of muscle spasms. It is especially useful in treating muscle spasticity associated with spinal cord injury. It appears to act primarily at the spinal cord level by inhibiting spinal polysynaptic afferent pathways and, to a lesser extent, monosynaptic afferent pathways.
Compound Type
  • Amine
  • Drug
  • GABA Agonist
  • Metabolite
  • Muscle Relaxant
  • Muscle Relaxant, Central
  • Muscle Relaxant, Skeletal
  • Neuromuscular Agent
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(+-)-Baclofen
4-Amino-3-(4-chlorophenyl)butyric acid
Baclofene
Baclofeno
Baclofenum
Baclon
beta-(4-Chlorophenyl)gaba
beta-(Aminomethyl)-4-chlorobenzenepropanoic acid
beta-(Aminomethyl)-P-chlorohydrocinnamic acid
beta-(P-Chlorophenyl)-gamma-aminobutyric acid
DL-4-Amino-3-P-chlorophenylbutanoic acid
DL-Baclofen
Gablofen
gamma-Amino-beta-(P-chlorophenyl)butyric acid
Kemstro
Lioresal
Lioresal Intrathecal
Nu-Baclofen
Pms-Baclofen
Chemical FormulaC10H12ClNO2
Average Molecular Mass213.661 g/mol
Monoisotopic Mass213.056 g/mol
CAS Registry Number1134-47-0
IUPAC Name4-amino-3-(4-chlorophenyl)butanoic acid
Traditional Namebaclofen
SMILESNCC(CC(O)=O)C1=CC=C(Cl)C=C1
InChI IdentifierInChI=1/C10H12ClNO2/c11-9-3-1-7(2-4-9)8(6-12)5-10(13)14/h1-4,8H,5-6,12H2,(H,13,14)
InChI KeyInChIKey=KPYSYYIEGFHWSV-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentGamma amino acids and derivatives
Alternative Parents
Substituents
  • Gamma amino acid or derivatives
  • 3-phenylpropanoic-acid
  • Amino fatty acid
  • Chlorobenzene
  • Aralkylamine
  • Halobenzene
  • Aryl chloride
  • Aryl halide
  • Monocyclic benzene moiety
  • Fatty acyl
  • Benzenoid
  • Amino acid
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Organohalogen compound
  • Organic nitrogen compound
  • Primary aliphatic amine
  • Organooxygen compound
  • Primary amine
  • Hydrocarbon derivative
  • Amine
  • Carbonyl group
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Organochloride
  • Organonitrogen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceBaclofen occurs as white to off-white crystals (8).
Experimental Properties
PropertyValue
Melting Point206-208°C
Boiling PointNot Available
Solubility2090 mg/L
LogP1.3
Predicted Properties
PropertyValueSource
Water Solubility0.71 g/LALOGPS
logP-0.82ALOGPS
logP-0.78ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)3.89ChemAxon
pKa (Strongest Basic)9.79ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity54.83 m³·mol⁻¹ChemAxon
Polarizability21.13 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-9600000000-6ae6d753213a9472b32cView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-0ff0-9720000000-6949ab5f0b56c63b916aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-03dr-0950000000-33d21cbb6740c1f1aee1View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-03di-1590000000-8a64733764308ba98f9aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-0f6t-0900000000-6647c58db763b4df68a0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-0udi-0900000000-72d6d878c9c2f29d846aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-014i-1900000000-18f69033596a03ee643aView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QQ , positivesplash10-014i-1900000000-997473c303f07afcdf4eView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-IT , positivesplash10-0002-0900000000-d1da4625d180fe0af521View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-03di-0190000000-bd0fff49defde62ed0faView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0ik9-0790000000-1a50b0b7f24aaaf6a87eView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01ot-0930000000-4c6fbeef09787ebe54c8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-016s-0900000000-904b104c639269bfe4f1View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-1900000000-62cafb0d9fec846e47b9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03xr-0690000000-4dd9b649eccb58c3cef0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03xr-0940000000-08d03c01d7cee16a2833View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0ikl-1900000000-69e953c6f51f0939e70cView in MoNA
MSMass Spectrum (Electron Ionization)splash10-000i-2900000000-963f049a4367a1d5a5f5View in MoNA
Toxicity Profile
Route of ExposureInhalation (9); ingestion (9); eye contact (9); dermal (9) Rapidly and almost completely absorbed from the GI tract.
Mechanism of ToxicityBaclofen is a direct agonist at GABAB receptors. The precise mechanism of action of Baclofen is not fully known. It is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect.
Metabolism~ 15% of the dose is metabolized in the liver, primarily by deamination. 70-80% of the dose is excreted unchanged or as metabolites in urine and the remainder is excreted in feces. Oral Baclofen is readily absorbed from the gastrointestinal tract. After oral administration, baclofen appears in the blodd within half an our. It is fairly distributed in most organs and body tissues. After oral administration of baclofen, about 85% is excreted unchanged in the urine and feces and the remainder is oxidatively dearninated in the liver to produce beta-(p-chlorophenyl)-gamma-hydroxybutyric acid as a major metabolite. (11). Route of Elimination: In a study using radiolabeled baclofen, approximately 85% of the dose was excreted unchanged in the urine and feces. Baclofen is excreted primarily by the kidney as unchanged drug; 70 - 80% of a dose appears in the urine as unchanged drug. The remainder is excreted as unchanged drug in the feces or as metabolites in the urine and feces. Half Life: 2.5-4 hours
Toxicity ValuesLD50: 45 mg/kg (Intravenous, Mouse) (1) LD50: 78 mg/kg (Intravenous, Rat) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the alleviation of signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity.
Minimum Risk LevelNot Available
Health EffectsHealth effects include hypertonia, hyperthermia, formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia, extreme muscle rigidity resembling neuroleptic malignant syndrome and rebound spasticity (6).
SymptomsLD50=45 mg/kg (male mice, IV); LD50=78 mg/kg (male rat, IV)
TreatmentTreatment may involve "pumping" the stomach, inducing vomiting, administering an antidote, and providing supportive care. (7)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00181
HMDB IDHMDB14327
PubChem Compound ID2284
ChEMBL IDCHEMBL701
ChemSpider ID2197
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID2972
BioCyc IDNot Available
CTD IDD001418
Stitch IDBaclofen
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkBaclofen
References
Synthesis Reference

Wayne Levadoux, Denis Groleau, Michael Trani, Robert Lortie, “Streptomyces microorganism useful for the preparation of®-baclofen from the racemic mixture.” U.S. Patent US5843765, issued April, 1994.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Mezler M, Muller T, Raming K: Cloning and functional expression of GABA(B) receptors from Drosophila. Eur J Neurosci. 2001 Feb;13(3):477-86. [11168554 ]
  3. Dzitoyeva S, Dimitrijevic N, Manev H: Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5485-90. Epub 2003 Apr 11. [12692303 ]
  4. See S, Ginzburg R: Skeletal muscle relaxants. Pharmacotherapy. 2008 Feb;28(2):207-13. doi: 10.1592/phco.28.2.207. [18225966 ]
  5. Gelber DA and Jeffery DR. Clinical evaluation and management of spasticity. Totowa, NJ: Humana Press.
  6. Wikipedia. Baclofen. Last Updated 6 July 2009. [Link]
  7. Monson, M (2009). Baclofen Overdose. [Link]
  8. Stability-Indicating HPLC Methods for Drug Analysis (2009). Baclofen. [Link]
  9. ScienceLab.com (2008). Material Safety Data Sheet (MSDS) for Baclofen. [Link]
  10. Drugs.com [Link]
  11. Drugs.com [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
G-protein coupled gaba receptor activity
Specific Function:
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. 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. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen.Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.
Gene Name:
GABBR1
Uniprot ID:
Q9UBS5
Molecular Weight:
108319.4 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. Stringer JL, Lorenzo N: The reduction in paired-pulse inhibition in the rat hippocampus by gabapentin is independent of GABA(B) receptor receptor activation. Epilepsy Res. 1999 Feb;33(2-3):169-76. [10094428 ]
  3. Garcia-Gil L, de Miguel R, Romero J, Perez A, Ramos JA, Fernandez-Ruiz JJ: Perinatal delta9-tetrahydrocannabinol exposure augmented the magnitude of motor inhibition caused by GABA(B), but not GABA(A), receptor agonists in adult rats. Neurotoxicol Teratol. 1999 May-Jun;21(3):277-83. [10386831 ]
  4. Motalli R, Louvel J, Tancredi V, Kurcewicz I, Wan-Chow-Wah D, Pumain R, Avoli M: GABA(B) receptor activation promotes seizure activity in the juvenile rat hippocampus. J Neurophysiol. 1999 Aug;82(2):638-47. [10444662 ]
  5. Mott DD, Li Q, Okazaki MM, Turner DA, Lewis DV: GABAB-Receptor-mediated currents in interneurons of the dentate-hilus border. J Neurophysiol. 1999 Sep;82(3):1438-50. [10482760 ]
  6. Ogasawara T, Itoh Y, Tamura M, Mushiroi T, Ukai Y, Kise M, Kimura K: Involvement of cholinergic and GABAergic systems in the reversal of memory disruption by NS-105, a cognition enhancer. Pharmacol Biochem Behav. 1999 Sep;64(1):41-52. [10494996 ]
General Function:
G-protein coupled gaba receptor activity
Specific Function:
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. 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. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception.
Gene Name:
GABBR2
Uniprot ID:
O75899
Molecular Weight:
105820.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.015 uMNot AvailableBindingDB 50032964
IC500.035 uMNot AvailableBindingDB 24182
IC501.77 uMNot AvailableBindingDB 50032963
References
  1. Filippov AK, Couve A, Pangalos MN, Walsh FS, Brown DA, Moss SJ: Heteromeric assembly of GABA(B)R1 and GABA(B)R2 receptor subunits inhibits Ca(2+) current in sympathetic neurons. J Neurosci. 2000 Apr 15;20(8):2867-74. [10751439 ]
  2. Martin SC, Russek SJ, Farb DH: Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1. Mol Cell Neurosci. 1999 Mar;13(3):180-91. [10328880 ]
  3. Jones KA, Tamm JA, Craig DA, Ph D, Yao W, Panico R: Signal transduction by GABA(B) receptor heterodimers. Neuropsychopharmacology. 2000 Oct;23(4 Suppl):S41-9. [11008066 ]
  4. Belley M, Sullivan R, Reeves A, Evans J, O'Neill G, Ng GY: Synthesis of the nanomolar photoaffinity GABA(B) receptor ligand CGP 71872 reveals diversity in the tissue distribution of GABA(B) receptor forms. Bioorg Med Chem. 1999 Dec;7(12):2697-704. [10658574 ]
  5. Braun M, Wendt A, Buschard K, Salehi A, Sewing S, Gromada J, Rorsman P: GABAB receptor activation inhibits exocytosis in rat pancreatic beta-cells by G-protein-dependent activation of calcineurin. J Physiol. 2004 Sep 1;559(Pt 2):397-409. Epub 2004 Jul 2. [15235087 ]
  6. Froestl W, Mickel SJ, Hall RG, von Sprecher G, Strub D, Baumann PA, Brugger F, Gentsch C, Jaekel J, Olpe HR, et al.: Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists. J Med Chem. 1995 Aug 18;38(17):3297-312. [7650684 ]
General Function:
G-protein coupled adenosine receptor activity
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction.
Gene Name:
ADORA3
Uniprot ID:
P0DMS8
Molecular Weight:
36184.175 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.05 uMNot AvailableBindingDB 24182
References
  1. Minetti P, Tinti MO, Carminati P, Castorina M, Di Cesare MA, Di Serio S, Gallo G, Ghirardi O, Giorgi F, Giorgi L, Piersanti G, Bartoccini F, Tarzia G: 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization. J Med Chem. 2005 Nov 3;48(22):6887-96. [16250647 ]