DrugBank: Tiagabine (DB00906)

targets (1) enzymes (1)

Identification

Name

Tiagabine

Accession Number

DB00906 (APRD00344)

Type

small molecule

Groups

approved

Description

Tiagabine is an anti-convulsive medication. It is also used in the treatment for panic disorder as are a few other anticonvulsants. Though the exact mechanism by which tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Tiagabina [INN-Spanish]
Tiagabinum [INN-Latin]

Brand names

Gabitril

Brand name mixtures

Not Available

Categories

GABA Agonists
Anticonvulsants
Neuroprotective Agents
Neurotransmitter Uptake Inhibitors

CAS number

115103-54-3

Weight

Average: 375.548
Monoisotopic: 375.132670429

Chemical Formula

C₂₀H₂₅NO₂S₂

InChI Key

InChIKey=PBJUNZJWGZTSKL-MRXNPFEDSA-N

InChI

InChI=1S/C20H25NO2S2/c1-14-7-11-24-18(14)17(19-15(2)8-12-25-19)6-4-10-21-9-3-5-16(13-21)20(22)23/h6-8,11-12,16H,3-5,9-10,13H2,1-2H3,(H,22,23)/t16-/m1/s1

Plain Text

IUPAC Name

(3R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-en-1-yl]piperidine-3-carboxylic acid

SMILES

CC1=C(SC=C1)C(=CCCN1CCC[C@H](C1)C(O)=O)C1=C(C)C=CS1

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Piperidines

Substructures

Hydroxy Compounds
Alkanes and Alkenes
Acetates
Carboxylic Acids and Derivatives
Aliphatic and Aryl Amines
Isoprenes
Heterocyclic compounds
Aromatic compounds
Thiophenes
Piperidines

Pharmacology

Indication

For the treatment of partial seizures

Pharmacodynamics

Tiagabine is used primarily as an anticonvulsant for the adjunctive treatment of epilepsy. The precise mechanism by which Tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine binds to recognition sites associated with the GABA uptake carrier. It is thought that, by this action, Tiagabine blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells.

Mechanism of action

Though the exact mechanism by which Tiagabine exerts its effect on the human body is unknown, it does appear to operate as a selective GABA reuptake inhibitor.

Absorption

Tiagabine is nearly completely absorbed (>95%).

Volume of distribution

Not Available

Protein binding

96%

Metabolism

Tiagabine is likely metabolized primarily by the 3A isoform subfamily of hepatic cytochrome P450.

Enzyme	Metabolite	Reaction	K_m	V_max
Cytochrome P450 3A4	Unknown	oxidation	0	0

Route of elimination

Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively, primarily as metabolites.

Half life

7-9 hours

Clearance

109 mL/min [Healthy subjects]

Toxicity

mptoms most often accompanying tiagabine overdose, alone or in combination with other drugs, have included: seizures including status epilepticus in patients with and without underlying seizure disorders, nonconvulsive status epilepticus, coma, ataxia, confusion, somnolence, drowsiness, impaired speech, agitation, lethargy, myoclonus, spike wave stupor, tremors, disorientation, vomiting, hostility, and temporary paralysis. Respiratory depression was seen in a number of patients, including children, in the context of seizures.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Cephalon inc

Packagers

Dosage forms

Form	Route	Strength
Tablet	Oral

Prices

Unit description	Cost	Unit
Gabitril 16 mg tablet	12.53 USD	tablet
Gabitril 12 mg tablet	6.4 USD	tablet
Gabitril 2 mg tablet	4.89 USD	tablet
Gabitril 4 mg tablet	3.9 USD	tablet

Patents

Country	Patent Number	Approved	Expires
United States	5958951	1997-06-10	2017-06-10
United States	5010090	1994-09-30	2011-09-30

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
logP	2.6	PhysProp

Predicted Properties

Property	Value	Source
water solubility	2.11e-02 g/l	ALOGPS
logP	4.98	ALOGPS
logP	2.47	ChemAxon Molconvert
logS	-4.25	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	3	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	40.54	ChemAxon Molconvert
rotatable bond count	6	ChemAxon Molconvert
refractivity	115.32	ChemAxon Molconvert
polarizability	41.70	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Compound	C07503
PubChem Compound	60648
PubChem Substance	46505560
ChemSpider	54661
BindingDB	50039251
Therapeutic Targets Database	DAP000164
PharmGKB	PA451682
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic/gabitril.htm
Drugs.com	http://www.drugs.com/cdi/tiagabine.html
Wikipedia	http://en.wikipedia.org/wiki/Tiagabine

ATC Codes

N03AG06

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

show (251.3 KB)

MSDS

Not Available

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. Sodium- and chloride-dependent GABA transporter 1 Pharmacological action: yes Actions: inhibitor Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals Organism class: human UniProt ID: P30531 Gene: SLC6A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K: The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin Psychiatry. 2005 Nov;66(11):1401-8. Pubmed Sheehan DV, Sheehan KH, Raj BA, Janavs J: An open-label study of tiagabine in panic disorder. Psychopharmacol Bull. 2007;40(3):32-40. Pubmed Foster AC, Kemp JA: Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17. Epub 2005 Dec 22. Pubmed Sunol C, Babot Z, Cristofol R, Sonnewald U, Waagepetersen HS, Schousboe A: A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures. Neurochem Res. 2010 Sep;35(9):1384-90. Epub 2010 May 30. Pubmed Henjum S, Hassel B: High-affinity GABA uptake and GABA-metabolizing enzymes in pig forebrain white matter: a quantitative study. Neurochem Int. 2007 Jan;50(2):365-70. Epub 2006 Oct 27. Pubmed

Targets

1. Sodium- and chloride-dependent GABA transporter 1

Pharmacological action: yes
Actions: inhibitor

Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: P30531 Link_out

Gene: SLC6A1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, Rickels K: The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin Psychiatry. 2005 Nov;66(11):1401-8. Pubmed
Sheehan DV, Sheehan KH, Raj BA, Janavs J: An open-label study of tiagabine in panic disorder. Psychopharmacol Bull. 2007;40(3):32-40. Pubmed
Foster AC, Kemp JA: Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17. Epub 2005 Dec 22. Pubmed
Sunol C, Babot Z, Cristofol R, Sonnewald U, Waagepetersen HS, Schousboe A: A possible role of the non-GAT1 GABA transporters in transfer of GABA from GABAergic to glutamatergic neurons in mouse cerebellar neuronal cultures. Neurochem Res. 2010 Sep;35(9):1384-90. Epub 2010 May 30. Pubmed
Henjum S, Hassel B: High-affinity GABA uptake and GABA-metabolizing enzymes in pig forebrain white matter: a quantitative study. Neurochem Int. 2007 Jan;50(2):365-70. Epub 2006 Oct 27. Pubmed

Enzymes
1. Cytochrome P450 3A4 Actions: substrate Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684 Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out

Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:44

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.