Gabapentin
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Basic Info
| Common Name | Gabapentin(F04774) |
| 2D Structure | |
| Description | Gabapentin 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. (A7831). |
| FRCD ID | F04774 |
| CAS Number | 60142-96-3 |
| PubChem CID | 3446 |
| Formula | C9H17NO2 |
| IUPAC Name | 2-[1-(aminomethyl)cyclohexyl]acetic acid |
| InChI Key | UGJMXCAKCUNAIE-UHFFFAOYSA-N |
| InChI | InChI=1S/C9H17NO2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10H2,(H,11,12) |
| Canonical SMILES | C1CCC(CC1)(CC(=O)O)CN |
| Isomeric SMILES | C1CCC(CC1)(CC(=O)O)CN |
| Wikipedia | Gabapentin |
| Synonyms |
1-(Aminomethyl)cyclohexaneacetic acid
gabapentin
60142-96-3
Neurontin
Gabapentine
Aclonium
Gabapentinum
Gabapetin
2-[1-(aminomethyl)cyclohexyl]acetic acid
Gabapentino
|
| Classifies |
Predicted: Pollutant
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Organic acids and derivatives |
| Class | Carboxylic acids and derivatives |
| Subclass | Amino acids, peptides, and analogues |
| Intermediate Tree Nodes | Amino acids and derivatives |
| Direct Parent | Gamma amino acids and derivatives |
| Alternative Parents | |
| Molecular Framework | Aliphatic homomonocyclic compounds |
| 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 |
| Description | This compound 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. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 171.24 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 3 |
| Complexity | 162 |
| Monoisotopic Mass | 171.126 |
| Exact Mass | 171.126 |
| XLogP | -1.1 |
| Formal Charge | 0 |
| Heavy Atom Count | 12 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB+ | 0.9382 |
| Human Intestinal Absorption | HIA+ | 0.9410 |
| Caco-2 Permeability | Caco2- | 0.7271 |
| P-glycoprotein Substrate | Non-substrate | 0.6557 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.9789 |
| Non-inhibitor | 0.8866 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.7982 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.5525 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.8930 |
| CYP450 2D6 Substrate | Non-substrate | 0.8124 |
| CYP450 3A4 Substrate | Non-substrate | 0.7612 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.9409 |
| CYP450 2C9 Inhibitor | Non-inhibitor | 0.9273 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9418 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9547 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.8438 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.9706 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9406 |
| Non-inhibitor | 0.8659 | |
| AMES Toxicity | Non AMES toxic | 0.9162 |
| Carcinogens | Non-carcinogens | 0.8536 |
| Fish Toxicity | Low FHMT | 0.7853 |
| Tetrahymena Pyriformis Toxicity | Low TPT | 0.5968 |
| Honey Bee Toxicity | Low HBT | 0.5457 |
| Biodegradation | Not ready biodegradable | 0.7046 |
| Acute Oral Toxicity | III | 0.4759 |
| Carcinogenicity (Three-class) | Warning | 0.5375 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -2.1301 | LogS |
| Caco-2 Permeability | 1.1661 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 1.6472 | LD50, mol/kg |
| Fish Toxicity | 3.0727 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | -0.6186 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Is mannitol the treatment of choice for patients with ciguatera fish poisoning? | Clin Toxicol (Phila) | 2017 Nov | 28535116 |
| Dietary and pharmacological treatment of abdominal pain in IBS. | Gut | 2017 May | 28232472 |
| Clinical pharmacology of analgesic drugs in cattle. | Vet Clin North Am Food Anim Pract | 2015 Mar | 25578387 |
| Glutamic acid decarboxylase gene disruption reveals signalling pathway(s)governing complex morphogenic and metabolic events in Trichoderma atroviride. | Antonie Van Leeuwenhoek | 2013 Nov | 23912446 |
| A review of analgesic compounds used in food animals in the United States. | Vet Clin North Am Food Anim Pract | 2013 Mar | 23438397 |
| Pharmacokinetics and milk secretion of gabapentin and meloxicam co-administeredorally in Holstein-Friesian cows. | J Vet Pharmacol Ther | 2013 Feb | 22372845 |
| Update on treatment of essential tremor. | Curr Treat Options Neurol | 2013 Aug | 23881742 |
| Metabolic and toxicological considerations for the latest drugs used to treatirritable bowel syndrome. | Expert Opin Drug Metab Toxicol | 2013 Apr | 23330973 |
| Multiple sclerosis. | BMJ Clin Evid | 2012 Feb 10 | 22321967 |
| Are antiepileptic drugs used in the treatment of migraine associated with anincreased risk of suicidality? | Curr Pain Headache Rep | 2011 Jun | 21479999 |
| Implications of current clinical trials focused on medication overuse andtherapeutic prophylaxis. | Headache | 2011 Jul-Aug | 21770931 |
| Postherpetic neuralgia. | BMJ Clin Evid | 2010 Oct 8 | 21418680 |
| Cluster headache. | BMJ Clin Evid | 2010 Feb 9 | 21718584 |
| Diagnosis and treatment of osteoarthritis. | Top Companion Anim Med | 2010 Feb | 20188335 |
| Multiple sclerosis. | BMJ Clin Evid | 2009 May 14 | 21733201 |
| Gabapentin-induced delirium and dependence. | J Psychiatr Pract | 2009 Jul | 19625887 |
| Adjunctive topiramate enhances the risk of hypothermia associated with valproicacid therapy. | J Clin Pharm Ther | 2008 Oct | 18834366 |
| Development and application of a validated HPLC method for the analysis ofdissolution samples of gabapentin drug products. | J Pharm Biomed Anal | 2008 Jan 7 | 17935923 |
| Cluster headache. | BMJ Clin Evid | 2008 Feb 15 | 19450329 |
| Essential tremor. | BMJ Clin Evid | 2007 May 1 | 19454072 |
Targets
- 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
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]
- 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
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]
- Uniprot ID:
- Q5SQC4
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]
References
- 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:
- 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
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]
- 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
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]
- 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
- Mechanism of Action:
- Gabapentin 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.
References
- 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 ]