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HomeProduct name listGabapentin

Gabapentin

Synonym(s):1-(Aminomethyl)-cyclohexaneacetic acid;Gabapentin - CAS 60142-96-3 - Calbiochem;L-type Voltage Gated Ca2+ Channel Blocke, Gabapentin;Neurontin

  • CAS NO.:60142-96-3
  • Empirical Formula: C9H17NO2
  • Molecular Weight: 171.24
  • MDL number: MFCD00865286
  • EINECS: 262-076-3
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-02 10:08:32
Gabapentin Structural

What is Gabapentin?

Absorption

Gabapentin absorption occurs exclusively through facilitated transport by the LAT1 transporter in the intestines. This saturable process results in oral bioavailability that is inversely proportional to the administered dose; for instance, a 900 mg/day regimen has an approximate bioavailability of 60%, while a 4800 mg/day regimen drops to about 27%. The time to reach maximum concentration (Tmax) for gabapentin is estimated to be 2-3 hours. Notably, food intake does not significantly affect gabapentin absorption.

Toxicity

The oral TDLo of gabapentin in humans is 2.86 mg/kg and the LD50 in rats has been found to be >8000 mg/kg. Symptoms of overdose are consistent with the drug's adverse effect profile and involve CNS depression (e.g. dizziness, drowsiness, slurred speech, lethargy, loss of consciousness) and gastrointestinal symptoms such as diarrhea. Management of overdose should involve symptomatic and supportive treatment. Gabapentin can be removed by hemodialysis - this may be of benefit in some patients, such as those with impaired renal function.
Multi-drug overdoses involving gabapentin, particularly in combination with other CNS depressants such as opioids, can result in coma and death - this possibility should be considered when managing overdosage.

Description

Gabapentin was introduced in 1993 in the UK and early 1994 in the USA as an adjunctive therapy in the treatment of refractory partial seizures and secondarily generalized tonic-clonic seizures. Although being a lipophilic analog of the neurotransmitter GABA, gabapentin appears to exert its anticonvulsive function by a GABA receptor independent mechanism, possibly involving the L-system amino acid transporter protein. Gabapentin easily crosses the blood brain barrier and exhibits a favorable pharmacokinetic profile with high tolerability. It does not interfere with the metabolism of other concomitant administered antiepileptic drugs, thus having a low potential for drug interactions. Studies are currently underway for the use of gabapentin as mono-therapy for the treatment of various seizures.

Description

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter that functions by binding to the GABA receptors located in the spinal cord. Gabapentin is a γ-aminobutyric acid (GABA) analogue that acts as an anticonvulsant with proven analgesic effects in various neuropathic pain syndromes such as Complex Regional Pain Syndrome type one (CRPS 1). It is also prescribed to multiple sclerosis patients to control dysesthesias and may be useful in reducing neuropathic pain caused by cancer and HIV infection. It does not bind to GABA receptors, does not influence neural uptake of GABA, and does not inhibit the GABA-metabolizing enzyme, GABA transaminase. Unlike GABA, which does not pass through the blood-brain barrier, gabapentin penetrates into the central nervous system and binds to the α2δ-type voltage-gated calcium channels. The mechanism for the analgesic and anticonvulsant effects of gabapentin are not known.

Chemical properties

White Crystalline Solid

Originator

Warner-Lambert (U.S.A.)

The Uses of Gabapentin

Gabapentin is an Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant.

The Uses of Gabapentin

antipsychotic, 5HT2A antagonist

The Uses of Gabapentin

selective H1-receptor antagonist

The Uses of Gabapentin

For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).

Background

Gabapentin, a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), was first approved for use in the United States in 1993. Initially developed as an anti-epileptic medication for treating certain types of seizures, it is now also widely utilized for neuropathic pain. Gabapentin offers several advantages over other anti-epileptics, including a relatively benign adverse effect profile, a wide therapeutic index, and minimal metabolism, which reduces the likelihood of pharmacokinetic drug interactions. It is structurally and functionally related to another GABA derivative, pregabalin.

Indications

In the United States, gabapentin is officially indicated for the treatment of postherpetic neuralgia in adults and for the adjunctive treatment of partial-onset seizures, with or without secondary generalization, in patients 3 years of age and older. In Europe, gabapentin is indicated for adjunctive therapy in the treatment of partial-onset seizures, with or without secondary generalization, in patients 6 years of age and older and as monotherapy in patients 12 years of age and older. It is also used in adults for the treatment of various types of peripheral neuropathic pain, such as painful diabetic neuropathy.

What are the applications of Application

Gabapentin is a compound structurally similar to GABA that binds to voltage-sensitive Ca2+ channels

Definition

ChEBI: A gamma-amino acid that is cyclohexane substituted at position 1 by aminomethyl and carboxymethyl groups. Used for treatment of neuropathic pain and restless legs syndrome.

Indications

Gabapentin (Neurontin) significantly decreases pain scores and sleep interference associated with PHN. An initial dose of 300 mg/day is increased over 4 weeks (900, 1,800, 2,400, 3,600 mg/day divided t.i.d.) until efficacy is obtained or side effects become intolerable.

Manufacturing Process

32.8 g 1,1-cyclohexane-diacetic anhydride are mixed with 7 g anhydrous methanol and heated under reflux for 1 hour. After evaporation of the reaction mixture in a vacuum, was obtained 37.5 g monomethyl 1,1-cyclohexanediacetate in the form of a yellowish oil.
5.6 ml triethylamine in 16 ml anhydrous acetone are added dropwise at 0°C to a solution of 7.28 g monomethyl 1,1-cyclohexane-diacetate, then a solution of 3.6 ml ethyl chloroformate in 16 ml anhydrous acetone is added thereto. The reaction mixture is further stirred for 30 min at 0°C and and then a solution of 3.4 g sodium azide in 12 ml water added dropwise thereto. The reaction mixture is stirred for 1 hour at 0°C, then poured into ice water and extracted three times with 50 ml amounts of ice-cold toluene. The combined extracts are dried over anhydrous sodium sulphate at 0°C and subsequently introduced drop-wise into a flask pre-heated to 100°C. The mixture is then heated for a further hour under reflux and thereafter evaporated in a vacuum. The crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remains behind is heated under reflux for 3 hours with 50 ml 20% hydrochloric acid. After cooling the solution, it is extracted three times with 100 ml amounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam formed as a by-product product and the aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid crystallises as the hydrochloride; m.p. 117-118°C, after recrystallisation from acetone/methanol/ether. After recrystallization from methanol/ether the melting point of the product is 129-133°C.
By treatment with a basic ion exchanger and crystallisation from ethanol/ether, there is obtained pure 1-amino-methyl-1-cyclohexane-acetic acid; melting point 162-166°C.

brand name

Neurontin (ParkeDavis); Neurontin (Pfizer).

Therapeutic Function

Anticonvulsant

Biological Functions

Gabapentin (Neurotonin) was initially designed to be a rigid analogue of GABA. When it was discovered to have antiepileptic properties, it was assumed that this activity was related to a GABAergic mechanism. However, subsequent studies have failed to show any GABAergic activity of gabapentin. Although it has not yet been possible to ascribe any definite mechanism to its antiepileptic activity, there is recent evidence that it may function as an agonist at GABAB receptors in the brain.
Gabapentin is recommended as adjunctive therapy in the treatment of partial seizures in adults.When used with other drugs, it appears to be an effective AED; it is usually not effective when employed alone for patients with severe seizures.
Gabapentin is generally well tolerated, with somnolence, dizziness, and ataxia the most commonly reported adverse effects. A low incidence of potentially serious side effects and no significant allergic reactions have been reported.

General Description

Gabapentin and its closely related analog pregabalin,(S)-3-isobutyl-GABA, are broad-spectrum anticonvulsantswith multiple mechanisms of action.24,51 Inaddition to modulating calcium influx and stimulateGABA biosynthesis as discussed earlier, they also competefor the biosynthesis of L-glutamic acid because oftheir structural similarity to L-leucine.51 Gabapentin andpregabalin have very little liability for causing metabolicbaseddrug–drug interactions, particularly when used incombination with other AEDs because they are not metabolizedin humans. More than 95% of the drug is excretedunchanged through the kidneys. However, there are somedifferences in their bioavailability. Unlike gabapentin,which exhibits 60% bioavailability when given in lowdoses because of intestinal uptake by a saturable smallneutral L-amino acid transporter, the absorption of pregabalinis almost complete (98%) and exhibits an ideal linear pharmacokinetic profile.24 This high bioavailability of pregabalincan be attributed to its closer structure similarity tothe essential amino acid, L-leucine.

Biological Activity

Anticonvulsant with several possible mechanisms of action. Increases GABA in the brain and binds to a novel site associated with voltage-sensitive Ca 2+ channels. Prevents neuronal death and is antinociceptive and anxiolytic.

Biochem/physiol Actions

Primary Targetα2δ subunit of L-type voltage gated Ca2+ channels

Pharmacokinetics

Gabapentin is an anti-convulsant medication that inhibits the release of excitatory neurotransmitters, allowing for its use against pathologic neurotransmission such as that seen in neuropathic pain and seizure disorders. It has a wide therapeutic index, with doses in excess of 8000 mg/kg failing to cause a fatal reaction in rats.
Gabapentin is ineffective in absence seizures and should be used in caution in patients with mixed seizure disorders involving absence seizures. Gabapentin has been associated with drug reaction with eosinophilia and systemic symptoms (DRESS), otherwise known as multi-organ hypersensitivity. This reaction can prove fatal and early symptoms such as fever, lymphadenopathy, and rash should be promptly investigated.

Clinical Use

Antiepileptic:
Adjunctive treatment of partial seizures with or without secondary generalisation
Neuropathic pain
Migraine prophylaxis (unlicensed)

Side Effects

Dose-limiting adverse effects include somnolence, dizziness, ataxia, peripheral edema, and infection (22).

Side Effects

Long-Term Side Effects of Gabapentin:

  • Mood changes.
  • Behavioral changes.
  • Depression.
  • Anxiety.
  • Memory loss.
  • Weakened muscles.

Synthesis

In the original synthesis (Goedecke) cyclohexenone is reacted with ethyl cyanoacetate in the presence of ammonia to yield the Guareschi salt, which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid which is transformed by to the corresponding anhydride with acetic anhydride. This anhydride is treated with methanol to yield the half ester 2- acetic acid, which is subjected to a Curtius type rearrangement to give the isocyanate 2-acetic acid. The desired compound is obtained by hydrolysis of 2-acetic acid with HCl, followed by hydrochloric salt removal via anion exchange .
Synthesis_60142-96-3

Veterinary Drugs and Treatments

Gabapentin may be useful as adjunctive therapy for refractory or complex partial seizures, or in the treatment of chronic pain in dogs or cats.

Drug interactions

Potentially hazardous interactions with other drugs
Antacids: reduce absorption.
Antidepressants: antagonism of anticonvulsive effect (convulsive threshold lowered); avoid with St John’s wort.
Antimalarials: anticonvulsant effect antagonised by mefloquine.
Antipsychotics: antagonism of anticonvulsive effect (convulsive threshold lowered).
Orlistat: possible increased risk of convulsions.

Metabolism

There is no evidence of gabapentin metabolism in humans. Gabapentin is eliminated unchanged solely by renal excretion.

References

1) Cheng et al. (2004), Does gabapentin act as an agonist at native GABA(B) receptors?; J. Biomed. Sci., 11 346 2) Lanneau et al. (2001), Gabapentin is not a GABAB receptor agonist; Neuropharmacology 41 965 3) Hendrich et al. (2008), Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin; Proc. Natl. Acad. Sci. USA, 105 3628

Properties of Gabapentin

Melting point: 162°C
Boiling point: 314.4±15.0 °C(Predicted)
Density  1.058±0.06 g/cm3(Predicted)
Flash point: 9℃
storage temp.  2-8°C
solubility  H2O: 10 mg/mL
form  solid
pka pKa1 (25°) 3.68; pKa2 10.70
color  off-white
Merck  14,4319
BRN  2359739
Stability: Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20°C for up to 3 months.
CAS DataBase Reference 60142-96-3(CAS DataBase Reference)
EPA Substance Registry System Cyclohexaneacetic acid, 1-(aminomethyl)- (60142-96-3)

Safety information for Gabapentin

Signal word Danger
Pictogram(s)
ghs
Flame
Flammables
GHS02
ghs
Skull and Crossbones
Acute Toxicity
GHS06
ghs
Exclamation Mark
Irritant
GHS07
ghs
Health Hazard
GHS08
GHS Hazard Statements H225:Flammable liquids
H315:Skin corrosion/irritation
H319:Serious eye damage/eye irritation
H335:Specific target organ toxicity, single exposure;Respiratory tract irritation
H360:Reproductive toxicity
H370:Specific target organ toxicity, single exposure
Precautionary Statement Codes P201:Obtain special instructions before use.
P210:Keep away from heat/sparks/open flames/hot surfaces. — No smoking.
P260:Do not breathe dust/fume/gas/mist/vapours/spray.
P261:Avoid breathing dust/fume/gas/mist/vapours/spray.
P280:Wear protective gloves/protective clothing/eye protection/face protection.
P311:Call a POISON CENTER or doctor/physician.
P301+P310:IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P305+P351+P338:IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.
P308+P313:IF exposed or concerned: Get medical advice/attention.
P370+P378:In case of fire: Use … for extinction.
P403+P235:Store in a well-ventilated place. Keep cool.

Computed Descriptors for Gabapentin

InChIKey UGJMXCAKCUNAIE-UHFFFAOYSA-N

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