Canmetcon
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Record Information
Version2.0
Creation Date2009-07-21 20:28:19 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2977
Identification
Common NameVigabatrin
ClassSmall Molecule
DescriptionVigabatrin is only found in individuals that have used or taken this drug. It is an analogue of gamma-aminobutyric acid. It is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for the catabolism of gamma-aminobutyric acid. (From Martindale The Extra Pharmacopoeia, 31st ed)It is believed that vigabatrin increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by irreversibly inhibiting enzymes that catabolize GABA (gamma-aminobutyric acid transaminase GABA-T) or block the reuptake of GABA into glia and nerve endings. Vigabatrin may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.
Compound Type
  • Amine
  • Anticonvulsant
  • Drug
  • Enzyme Inhibitor
  • GABA Agent
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
4-Amino-5-hexenoic acid
gamma-Vinyl GABA
gamma-Vinyl-gamma-aminobutyric acid
GVG
Sabril
Sabrilan
Sabrilex
Vigabatrina
Vigabatrine
Vigabatrinum
Chemical FormulaC6H11NO2
Average Molecular Mass129.157 g/mol
Monoisotopic Mass129.079 g/mol
CAS Registry Number60643-86-9
IUPAC Name4-aminohex-5-enoic acid
Traditional Namevigabatrin
SMILESNC(CCC(O)=O)C=C
InChI IdentifierInChI=1/C6H11NO2/c1-2-5(7)3-4-6(8)9/h2,5H,1,3-4,7H2,(H,8,9)
InChI KeyInChIKey=PJDFLNIOAUIZSL-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
  • Medium-chain fatty acid
  • Amino fatty acid
  • Unsaturated fatty acid
  • Fatty acyl
  • Fatty acid
  • Amino acid
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Amine
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxide
  • Primary aliphatic amine
  • Organopnictogen compound
  • Organic oxygen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic 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 Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility55.1 mg/mL
LogP-2.16
Predicted Properties
PropertyValueSource
Water Solubility96.6 g/LALOGPS
logP-2.6ALOGPS
logP-2.1ChemAxon
logS-0.13ALOGPS
pKa (Strongest Acidic)4.61ChemAxon
pKa (Strongest Basic)9.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity34.29 m³·mol⁻¹ChemAxon
Polarizability13.64 ųChemAxon
Number of Rings0ChemAxon
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, Positivesplash10-0a6r-9000000000-ed9483c326234125f4adView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-004i-3900000000-6c317e49ab8cc532a558View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9400000000-0215823a9ba364cc48cbView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9400000000-c7d21d36dfb8e7079ee2View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9200000000-e0c504f980ef5bbc0501View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9000000000-e1b2ea8d5a2da84a5a64View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9000000000-52958176067fd9bae916View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00di-9000000000-263da4b132ca66986967View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-01b9-9000000000-1f8826cc32ef269c1a7cView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-014i-9000000000-32306e2f90cd529accc7View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0gb9-9000000000-aefa9f2682087c7b78edView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01q9-3900000000-5bf6d0079fa19a719d28View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01q9-9400000000-1d89cce66d591018b8b6View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0gb9-9000000000-25ce972a542597293a60View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-2900000000-14e6a479b3001860431bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-7900000000-fd7f3b3f074734314a87View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4l-9100000000-db0d4ab6ed018a7e6a3fView in MoNA
Toxicity Profile
Route of ExposureRapidly absorbed following oral administration, absorption is comparable between neonates, infants, and children. Cmax, 50 mg/kg dose, neonates= 14 mg/L; Tmax, 50 mg/kg dose, neonates = 2.1 hours; However, extent of absorption is higher and elimination half life is longer in neonates compared to children and infants. This is because neonates have reduced renal function compared to the aforementioned population groups. AUC, 50 mg/kg dose, neonates = 142.6 ± 44.0 mg/L/hr; Food may slightly decrease the rate (Cmax decreased by 33%, Tmax increased to 2 hours), but not the extent of absorption. Furthermore, vigabatrin does not cross the blood-brain-barrier well, thus high doses are needed.
Mechanism of ToxicityVigabatrin increases brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by irreversibly inhibiting enzymes that catabolize GABA (gamma-aminobutyric acid transaminase, GABA-T). Duration of action is determined by rate of GABA-T re-synthesis. Vigabatrin may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. Although administered as a racemic mixture, only the S(+) enantiomer is pharmacologically active.
MetabolismAlmost no metabolic transformation. Does not induce the hepatic cytochrome P450 system. Route of Elimination: Eliminated primarily through renal excretion as unchanged drugs (80%). Half Life: Neonates, 50 mg/kg = 7.5 ± 2.1 hours (due to reduced renal function); Infants = 5.7 hours; Adults = 7.5 hours; Elderly = 12 - 13 hours
Toxicity ValuesLD50, oral, rat: 3000 mg/kg
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use as an adjunct in treatment resistant epilepsy, refractory complex partial seizures, and secondary generalized seizures. It is also used as monotherapy in infantile spasms in West syndrome.
Minimum Risk LevelNot Available
Health EffectsMay cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01080
HMDB IDHMDB15212
PubChem Compound ID5665
ChEMBL IDCHEMBL89598
ChemSpider ID5463
KEGG IDC07500
UniProt IDNot Available
OMIM ID
ChEBI ID63638
BioCyc IDVIGABATRIN
CTD IDNot Available
Stitch IDVigabatrin
PDB ID1OHW
ACToR IDNot Available
Wikipedia LinkVigabatrin
References
Synthesis ReferenceNot Available
MSDSLink
General References
  1. Gram L, Larsson OM, Johnsen A, Schousboe A: Experimental studies of the influence of vigabatrin on the GABA system. Br J Clin Pharmacol. 1989;27 Suppl 1:13S-17S. [2757904 ]
  2. Browne TR: Pharmacokinetics of antiepileptic drugs. Neurology. 1998 Nov;51(5 Suppl 4):S2-7. [9818917 ]
  3. Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T: Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit. 2003 Aug;25(4):457-62. [12883229 ]
  4. Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, Kathmann N, Schwarz M, Moller HJ, Rupprecht R: Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology. 2001 Nov;25(5):699-703. [11682253 ]
  5. Tulloch JK, Carr RR, Ensom MH: A systematic review of the pharmacokinetics of antiepileptic drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther. 2012 Jan;17(1):31-44. doi: 10.5863/1551-6776-17.1.31. [23118657 ]
  6. Clayton LM, Stern WM, Newman WD, Sander JW, Acheson J, Sisodiya SM: Evolution of visual field loss over ten years in individuals taking vigabatrin. Epilepsy Res. 2013 Aug;105(3):262-71. doi: 10.1016/j.eplepsyres.2013.02.014. Epub 2013 Mar 28. [23541931 ]
  7. Hawker DD, Silverman RB: Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. Bioorg Med Chem. 2012 Oct 1;20(19):5763-73. doi: 10.1016/j.bmc.2012.08.009. Epub 2012 Aug 16. [22944334 ]
  8. Drugs.com [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Succinate-semialdehyde dehydrogenase binding
Specific Function:
Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively. Can also convert delta-aminovalerate and beta-alanine.
Gene Name:
ABAT
Uniprot ID:
P80404
Molecular Weight:
56438.405 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory3200 uMNot AvailableBindingDB 50118886
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Weber OM, Verhagen A, Duc CO, Meier D, Leenders KL, Boesiger P: Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography. Magn Reson Imaging. 1999 Apr;17(3):417-25. [10195585 ]
  3. Valdizan EM, Garcia AP, Armijo JA: Effects of increasing doses of vigabatrin on platelet gamma-aminobutyric acid-transaminase and brain gamma-aminobutyric acid in rats. Eur J Pharmacol. 1999 Mar 19;369(2):169-73. [10206175 ]
  4. Arndt CF, Derambure P, Defoort-Dhellemmes S, Hache JC: Outer retinal dysfunction in patients treated with vigabatrin. Neurology. 1999 Apr 12;52(6):1201-5. [10214744 ]
  5. Molina PE, Ahmed N, Ajmal M, Dewey S, Volkow N, Fowler J, Abumrad N: Co-administration of gamma-vinyl GABA and cocaine: preclinical assessment of safety. Life Sci. 1999;65(11):1175-82. [10503933 ]
  6. French JA: Vigabatrin. Epilepsia. 1999;40 Suppl 5:S11-6. [10530689 ]
  7. Pan Y, Qiu J, Silverman RB: Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent gamma-aminobutyric acid aminotransferase inhibitor. J Med Chem. 2003 Dec 4;46(25):5292-3. [14640537 ]
  8. Pan Y, Gerasimov MR, Kvist T, Wellendorph P, Madsen KK, Pera E, Lee H, Schousboe A, Chebib M, Brauner-Osborne H, Craft CM, Brodie JD, Schiffer WK, Dewey SL, Miller SR, Silverman RB: (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent gamma-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. J Med Chem. 2012 Jan 12;55(1):357-66. doi: 10.1021/jm201231w. Epub 2011 Dec 30. [22128851 ]
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. Tyacke RJ, Lingford-Hughes A, Reed LJ, Nutt DJ: GABAB receptors in addiction and its treatment. Adv Pharmacol. 2010;58:373-96. doi: 10.1016/S1054-3589(10)58014-1. [20655489 ]