Chemical Properties
White Crystalline Solid
Originator
Warner-Lambert
(U.S.A.)
History
Gabapentin is a pharmacologically active amino acid, discovered by the pharmaceutical company Parke-Davis, now owned by Warner-Lambert, a division of Pfizer in 1974. Although it was first approved as a treatment for partial seizures in 1993, Pfizer pleaded guilty to illegally marketing gabapentin for unapproved uses in 2004 and was heavily fined by the US Department of Justice for defrauding public health care programs. When this adjunctive use was approved by the US Food and Drug Administration (FDA) in late 1993, Warner-Lambert released gabapentin under the brand name Neurontin, expecting it to make no more than $500,000. But the 2001 sales of Neurontin raked in $1.2 billion.
Uses
Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant.
Uses
antipsychotic, 5HT2A antagonist
Uses
For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).
Uses
selective H1-receptor antagonist
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.
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
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).
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 .
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
