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Record Information
Version2.0
Creation Date2009-07-21 20:28:07 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2952
Identification
Common NameGabapentin
ClassSmall Molecule
DescriptionGabapentin was originally developed as a chemical analogue of gamma-aminobutyric acid (GABA) to reduce the spinal reflex for the treatment of spasticity and was found to have anticonvulsant activity in various seizure models. In addition, it also displays antinociceptive activity in various animal pain models. Clinically, gabapentin is indicated as an add-on medication for the treatment of partial seizures, and neuropathic pain. It was also claimed to be beneficial in several other clinical disorders such as anxiety, bipolar disorder, and hot flashes. The possible mechanisms or targets involved in the multiple therapeutic actions of gabapentin have been actively studied. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA(B) receptors consisting of GABA(B1a) and GABA(B2) subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-alpha-amino acid transporter, activating ATP-sensitive K(+) channels, activating hyperpolarization-activated cation channels, and modulating Ca(2+) current by selectively binding to the specific binding site of [(3)H]gabapentin, the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the alpha(2)delta subunit of spinal N-type Ca(2+) channels is very likely the analgesic action target of gabapentin. (5).
Compound Type
  • Amine
  • Analgesic
  • Anti-Anxiety Agent
  • Anticonvulsant
  • Antimanic Agent
  • Antiparkinson Agent
  • Calcium Channel Blocker
  • Drug
  • Excitatory Amino Acid Antagonist
  • Food Toxin
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1-(Aminomethyl)cyclohexaneacetic acid
Aclonium
Gabapentin GR
Gabapentina
Gabapentine
Gabapentino
Gabapentinum
Gabapetin
Gralise
Neurontin
Novo-Gabapentin
Novo-Gabapentine
Chemical FormulaC9H17NO2
Average Molecular Mass171.237 g/mol
Monoisotopic Mass171.126 g/mol
CAS Registry Number60142-96-3
IUPAC Name2-[1-(aminomethyl)cyclohexyl]acetic acid
Traditional Namegabapentin
SMILESNCC1(CC(O)=O)CCCCC1
InChI IdentifierInChI=1S/C9H17NO2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10H2,(H,11,12)
InChI KeyInChIKey=UGJMXCAKCUNAIE-UHFFFAOYSA-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
  • Amino fatty acid
  • Fatty acyl
  • Amino acid
  • Carboxylic acid
  • Monocarboxylic acid or derivatives
  • Organopnictogen compound
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Primary aliphatic amine
  • Organic oxygen compound
  • Carbonyl group
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Aliphatic homomonocyclic compound
Molecular FrameworkAliphatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue Locations
  • Brain
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point162-166°C
Boiling PointNot Available
Solubility4490 mg/L
LogP-1.1
Predicted Properties
PropertyValueSource
Water Solubility4.34 g/LALOGPS
logP-1.9ALOGPS
logP-1.3ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)4.63ChemAxon
pKa (Strongest Basic)9.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area63.32 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity46.33 m³·mol⁻¹ChemAxon
Polarizability18.92 ųChemAxon
Number of Rings1ChemAxon
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, Positivesplash10-001i-9300000000-1b1c66a2b9ea4333921dJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-00ai-9520000000-9cbc5f48f228d49f903cJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-00di-0900000000-bccc9bd5f1637db7b6c7JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-00di-0900000000-67139ca9559173bf9859JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , negativesplash10-0006-9000000000-bfe6527f738e4c67eb2bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-00di-0900000000-bb175ef297a289e1936bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0udr-0900000000-258d4493623d0ab7b415JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0f79-0900000000-bc24764f394c6fee34fdJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0udi-0900000000-006ecd4a58af763b087fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-012c52738f11970adb8dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-8f0d390195aa406adb5dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0uk9-0900000000-72f8d5cb88eda76dab56JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0udi-3900000000-b634b4e7144ec6ffdc83JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0ktn-9800000000-20c4131179b228ab3440JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00ke-9300000000-dd9d44ed4f16961ed075JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-f9a7deaa778e9d893ee8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-4f85e6ac9fd91a3e3b81JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0uk9-0900000000-d3a4c5658e343cf3cf8dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0udi-3900000000-712133d5b9eae1b27ffbJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0ktn-9800000000-c652847259e0851b428eJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00ke-9200000000-77e258cf26b045a7e46eJSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0kmi-0900000000-bd606c1e84a1821141d5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a6r-1900000000-7e1f93e356d99c221d79JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4l-9400000000-e7cad8847543c27e9be7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00fr-0900000000-46b0ef53eef895d16407JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00fr-1900000000-49d03843c6afc2b38719JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-7900000000-21b2e487e51f606cc2adJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureOral. Rapid. Absorbed in part by the L-amino acid transport system, which is a carrier-mediated, saturable transport system; as the dose increases, bioavailability decreases. Bioavailability ranges from approximately 60% for a 900 mg dose per day to approximately 27% for a 4800 milligram dose per day. Food has a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC).
Mechanism of ToxicityGabapentin interacts with cortical neurons at auxillary subunits of voltage-sensitive calcium channels. Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters. One of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus. This is mediated through its binding to presynaptic NMDA receptors. Other studies have shown that the antihyperalgesic and antiallodynic effects of gabapentin are mediated by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors. Gabapentin has also been shown to bind and activate the adenosine A1 receptor.
MetabolismAll pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. Route of Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. Half Life: 5-7 hours
Toxicity ValuesLD50: >8000 mg/kg (oral,rat) [MSDS] LD50: 8053 mg/kg (oral, mouse) [MSDS]
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesIt was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain. [wikipedia]. For the management of postherpetic neuralgia in adults and as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy.
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.
SymptomsSymptoms of overdose include ataxia, labored breathing, ptosis, sedation, hypoactivity, and excitation.
TreatmentGabapentin can be removed by hemodialysis. (14)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00996
HMDB IDHMDB05015
PubChem Compound ID3446
ChEMBL IDCHEMBL940
ChemSpider ID3328
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID42797
BioCyc IDNot Available
CTD IDNot Available
Stitch IDGabapentin
PDB IDGBN
ACToR IDNot Available
Wikipedia LinkGabapentin
References
Synthesis Reference

Donald E. Butler, Barbara J. Greenman, “Gabapentin mohohydrate and a process for producing the same.” U.S. Patent US4960931, issued May, 1978.

MSDSLink
General References
  1. Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, Stacey B, Tepper S: Efficacy of gabapentin in migraine prophylaxis. Headache. 2001 Feb;41(2):119-28. [11251695 ]
  2. Backonja MM, Serra J: Pharmacologic management part 1: better-studied neuropathic pain diseases. Pain Med. 2004 Mar;5 Suppl 1:S28-47. [14996228 ]
  3. Choudhuri I, Sarvananthan N, Gottlob I: Survey of management of acquired nystagmus in the United Kingdom. Eye (Lond). 2007 Sep;21(9):1194-7. Epub 2006 May 26. [16732211 ]
  4. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G: Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord. 2000 Sep;2(3 Pt 2):249-55. [11249802 ]
  5. Cheng JK, Chiou LC: Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci. 2006;100(5):471-86. Epub 2006 Feb 11. [16474201 ]
  6. Su TZ, Feng MR, Weber ML: Mediation of highly concentrative uptake of pregabalin by L-type amino acid transport in Chinese hamster ovary and Caco-2 cells. J Pharmacol Exp Ther. 2005 Jun;313(3):1406-15. Epub 2005 Mar 15. [15769862 ]
  7. Nemeroff CB: The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull. 2003;37(4):133-46. [15131523 ]
  8. Di Trapani G, Mei D, Marra C, Mazza S, Capuano A: Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter. 2000 May-Jun;151(3):145-8. [10958046 ]
  9. Bisaga A, Aharonovich E, Garawi F, Levin FR, Rubin E, Raby WN, Nunes EV: A randomized placebo-controlled trial of gabapentin for cocaine dependence. Drug Alcohol Depend. 2006 Feb 28;81(3):267-74. Epub 2005 Oct 5. [16169160 ]
  10. Petroff OA, Rothman DL, Behar KL, Lamoureux D, Mattson RH: The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol. 1996 Jan;39(1):95-9. [8572673 ]
  11. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Dooley DJ, Boden P, Singh L: A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 1998 Feb;29(3):233-49. [9551785 ]
  12. Czapinski P, Blaszczyk B, Czuczwar SJ: Mechanisms of action of antiepileptic drugs. Curr Top Med Chem. 2005;5(1):3-14. [15638774 ]
  13. Drugs.com [Link]
  14. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Voltage-gated calcium channel activity
Specific Function:
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity).
Gene Name:
CACNA2D1
Uniprot ID:
P54289
Molecular Weight:
124566.93 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.027 uMNot AvailableBindingDB 50080153
References
  1. Gazulla J, Tintore MA: The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit. Med Hypotheses. 2007;68(1):131-6. Epub 2006 Aug 8. [16899342 ]
  2. Maneuf YP, Luo ZD, Lee K: alpha2delta and the mechanism of action of gabapentin in the treatment of pain. Semin Cell Dev Biol. 2006 Oct;17(5):565-70. Epub 2006 Sep 24. [17067834 ]
  3. Hota D, Bansal V, Pattanaik S: Evaluation of ketamine, nimodipine, gabapentin and imipramine in partial sciatic nerve transection model of neuropathic pain in rat: an experimental study. Methods Find Exp Clin Pharmacol. 2007 Sep;29(7):443-6. [17982508 ]
  4. Lim J, Stock N, Pracitto R, Boueres JK, Munoz B, Chaudhary A, Santini AM, Orr K, Schaffhauser H, Bezverkov RE, Aiyar J, Venkatraman S: N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels. Bioorg Med Chem Lett. 2004 Apr 19;14(8):1913-6. [15050626 ]
General Function:
Purine nucleoside binding
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:
ADORA1
Uniprot ID:
P30542
Molecular Weight:
36511.325 Da
References
  1. De Vry J, Kuhl E, Franken-Kunkel P, Eckel G: Pharmacological characterization of the chronic constriction injury model of neuropathic pain. Eur J Pharmacol. 2004 May 3;491(2-3):137-48. [15140630 ]
  2. Zuchora B, Wielosz M, Urbanska EM: Adenosine A1 receptors and the anticonvulsant potential of drugs effective in the model of 3-nitropropionic acid-induced seizures in mice. Eur Neuropsychopharmacol. 2005 Jan;15(1):85-93. [15572277 ]
  3. Kralic JE, Criswell HE, Osterman JL, O'Buckley TK, Wilkie ME, Matthews DB, Hamre K, Breese GR, Homanics GE, Morrow AL: Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice. J Clin Invest. 2005 Mar;115(3):774-9. [15765150 ]
General Function:
Voltage-gated calcium channel activity
Specific Function:
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis.
Gene Name:
CACNA2D2
Uniprot ID:
Q9NY47
Molecular Weight:
129816.095 Da
References
  1. Gazulla J, Tintore MA: The P/Q-type voltage-dependent calcium channel as pharmacological target in spinocerebellar ataxia type 6: gabapentin and pregabalin may be of therapeutic benefit. Med Hypotheses. 2007;68(1):131-6. Epub 2006 Aug 8. [16899342 ]
  2. Hota D, Bansal V, Pattanaik S: Evaluation of ketamine, nimodipine, gabapentin and imipramine in partial sciatic nerve transection model of neuropathic pain in rat: an experimental study. Methods Find Exp Clin Pharmacol. 2007 Sep;29(7):443-6. [17982508 ]
  3. Gong HC, Hang J, Kohler W, Li L, Su TZ: Tissue-specific expression and gabapentin-binding properties of calcium channel alpha2delta subunit subtypes. J Membr Biol. 2001 Nov 1;184(1):35-43. [11687876 ]
General Function:
L-valine transaminase activity
Specific Function:
Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine.
Gene Name:
BCAT1
Uniprot ID:
P54687
Molecular Weight:
42965.815 Da
References
  1. Goto M, Miyahara I, Hirotsu K, Conway M, Yennawar N, Islam MM, Hutson SM: Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin. J Biol Chem. 2005 Nov 4;280(44):37246-56. Epub 2005 Sep 1. [16141215 ]
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
Not Available
Uniprot ID:
Q5SQC4
Molecular Weight:
Not Available
References
  1. Oka M, Itoh Y, Wada M, Yamamoto A, Fujita T: Gabapentin blocks L-type and P/Q-type Ca2+ channels involved in depolarization-stimulated nitric oxide synthase activity in primary cultures of neurons from mouse cerebral cortex. Pharm Res. 2003 Jun;20(6):897-9. [12817894 ]
6. NMDA receptor (Protein Group)
General Function:
Voltage-gated cation channel activity
Specific Function:
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors (By similarity).
Included Proteins:
Q05586 , Q12879 , Q13224 , Q14957 , O15399 , Q8TCU5 , O60391
References
  1. Shimoyama M, Shimoyama N, Hori Y: Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain. 2000 Apr;85(3):405-14. [10781913 ]
General Function:
Voltage-gated calcium channel activity
Specific Function:
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1B gives rise to N-type calcium currents. N-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by omega-conotoxin-GVIA (omega-CTx-GVIA) and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to dihydropyridines (DHP), and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing alpha-1B subunit may play a role in directed migration of immature neurons.
Gene Name:
CACNA1B
Uniprot ID:
Q00975
Molecular Weight:
262493.84 Da
References
  1. Cheng JK, Chen CC, Yang JR, Chiou LC: The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors? Anesth Analg. 2006 Jan;102(1):182-7. [16368827 ]