T3DB: Vigabatrin

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Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (2)XML

Targets (2)

Record Information

Version

2.0

Creation Date

2009-07-21 20:28:19 UTC

Update Date

2014-12-24 20:25:54 UTC

Accession Number

T3D2977

Identification

Common Name

Vigabatrin

Class

Small Molecule

Description

Vigabatrin 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

MOL SDF PDB SMILES InChI

Synonyms

Synonym
4-Amino-5-hexenoic acid
gamma-Vinyl GABA
gamma-Vinyl-gamma-aminobutyric acid
GVG
Sabril
Sabrilan
Sabrilex
Vigabatrina
Vigabatrine
Vigabatrinum

Chemical Formula

C₆H₁₁NO₂

Average Molecular Mass

129.157 g/mol

Monoisotopic Mass

129.079 g/mol

CAS Registry Number

60643-86-9

IUPAC Name

4-aminohex-5-enoic acid

Traditional Name

vigabatrin

SMILES

NC(CCC(O)=O)C=C

InChI Identifier

InChI=1/C6H11NO2/c1-2-5(7)3-4-6(8)9/h2,5H,1,3-4,7H2,(H,8,9)

InChI Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Gamma 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 Framework

Aliphatic acyclic compounds

External Descriptors

gamma-amino acid (CHEBI:63638 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

anticonvulsant

Biological Roles

EC 2.6.1.19 (4-aminobutyrate--2-oxoglutarate transaminase) inhibitor

Chemical Roles

EC 2.6.1.19 (4-aminobutyrate--2-oxoglutarate transaminase) inhibitor

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	55.1 mg/mL
LogP	-2.16

Predicted Properties

Property	Value	Source
Water Solubility	96.6 g/L	ALOGPS
logP	-2.6	ALOGPS
logP	-2.1	ChemAxon
logS	-0.13	ALOGPS
pKa (Strongest Acidic)	4.61	ChemAxon
pKa (Strongest Basic)	9.91	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	63.32 Å²	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	34.29 m³·mol⁻¹	ChemAxon
Polarizability	13.64 Å³	ChemAxon
Number of Rings	0	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	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0a6r-9000000000-ed9483c326234125f4ad	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-004i-3900000000-6c317e49ab8cc532a558	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	JSpectraViewer
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	JSpectraViewer
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9400000000-0215823a9ba364cc48cb	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9400000000-c7d21d36dfb8e7079ee2	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9200000000-e0c504f980ef5bbc0501	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9000000000-e1b2ea8d5a2da84a5a64	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9000000000-52958176067fd9bae916	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-00di-9000000000-263da4b132ca66986967	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-01b9-9000000000-1f8826cc32ef269c1a7c	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-014i-9000000000-32306e2f90cd529accc7	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0gb9-9000000000-aefa9f2682087c7b78ed	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 90V, Positive	splash10-00di-9000000000-2e8122bd9fa086c48c81	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 60V, Positive	splash10-00di-9000000000-c89fa23e4a66cb1fda0e	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 75V, Positive	splash10-00di-9000000000-ee55e365ddd88597a424	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 120V, Positive	splash10-01b9-9000000000-59ee75afd49600cf9595	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 150V, Positive	splash10-014i-9000000000-32306e2f90cd529accc7	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 45V, Positive	splash10-00di-9200000000-6c0ed7a9357b20c8ddec	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-00di-9400000000-67f3710d9b1a8968c528	JSpectraViewer \| MoNA
LC-MS/MS	LC-MS/MS Spectrum - 180V, Positive	splash10-0gb9-9000000000-aefa9f2682087c7b78ed	JSpectraViewer \| MoNA
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-01q9-3900000000-5bf6d0079fa19a719d28	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-01q9-9400000000-1d89cce66d591018b8b6	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0gb9-9000000000-25ce972a542597293a60	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-004i-2900000000-14e6a479b3001860431b	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-004i-7900000000-fd7f3b3f074734314a87	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4l-9100000000-db0d4ab6ed018a7e6a3f	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-001i-9400000000-6179584a37d7e78d7234	JSpectraViewer
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-014i-9000000000-ff84f320ba47dd80531b	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer
1D NMR	1H NMR Spectrum	Not Available	JSpectraViewer
1D NMR	13C NMR Spectrum	Not Available	JSpectraViewer

Toxicity Profile

Route of Exposure

Rapidly 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 Toxicity

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). 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.

Metabolism

Almost 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 Values

LD50, oral, rat: 3000 mg/kg

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

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

Uses/Sources

For 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 Level

Not Available

Health Effects

May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease.

Symptoms

Not Available

Treatment

Not Available

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

63638

BioCyc ID

VIGABATRIN

CTD ID

Not Available

Stitch ID

Vigabatrin

PDB ID

1OHW

ACToR ID

Not Available

Wikipedia Link

Vigabatrin

References

Synthesis Reference

Not Available

MSDS

Link

General References

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 ]
Browne TR: Pharmacokinetics of antiepileptic drugs. Neurology. 1998 Nov;51(5 Suppl 4):S2-7. [9818917 ]
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 ]
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 ]
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 ]
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 ]
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 ]
Drugs.com [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. 4-aminobutyrate aminotransferase, mitochondrial

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

Type	Value	Assay Type	Assay Source
Inhibitory	3200 uM	Not Available	BindingDB 50118886

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
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 ]
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 ]
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 ]
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 ]
French JA: Vigabatrin. Epilepsia. 1999;40 Suppl 5:S11-6. [10530689 ]
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 ]
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 ]

Target Details

2. Gamma-aminobutyric acid type B receptor subunit 1

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

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 ]

Vigabatrin (T3D2977)

Structure for T3D2977: Vigabatrin

Targets

Binding/Activity Constants

References

References