Gabapentin

Bezeichnung:Gabapentin

CAS-Nr60142-96-3

Englisch Name:Gabapentin

CBNumberCB3263316

SummenformelC9H17NO2

Molgewicht171.24

MOL-Datei60142-96-3.mol

Synonyma

Gabapentin

Gabapentin physikalisch-chemischer Eigenschaften

Schmelzpunkt	162°C
Siedepunkt	314.4±15.0 °C(Predicted)
Dichte	1.058±0.06 g/cm3(Predicted)
Flammpunkt	9℃
storage temp.	2-8°C
Löslichkeit	H₂O: 10 mg/mL
Aggregatzustand	solid
pka	pKa1 (25°) 3.68; pKa2 10.70
Farbe	off-white
Wasserlöslichkeit	water: 100mM
Merck	14,4319
BRN	2359739
BCS Class	3
Stabilität	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.
InChIKey	UGJMXCAKCUNAIE-UHFFFAOYSA-N
CAS Datenbank	60142-96-3(CAS DataBase Reference)
EPA chemische Informationen	Cyclohexaneacetic acid, 1-(aminomethyl)- (60142-96-3)

Sicherheit

Kennzeichnung gefährlicher	T,Xi,F
R-Sätze:	61-36/37/38-39/23/24/25-23/24/25-11
S-Sätze:	53-26-36/37/39-45-36-36/37-16
WGK Germany	3
RTECS-Nr.	GU6496000
HazardClass	IRRITANT
HS Code	29224999
Giftige Stoffe Daten	60142-96-3(Hazardous Substances Data)

Gefahreninformationscode (GHS)

Gabapentin Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R61:Kann das Kind im Mutterleib schädigen.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-Sätze Betriebsanweisung:
S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
Beschreibung
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.
Beschreibung
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.
Chemische Eigenschaften
White Crystalline Solid
Originator
Warner-Lambert (U.S.A.)
Verwenden
Gabapentin is an Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant.
Verwenden
For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).
Verwenden
antipsychotic, 5HT2A antagonist
Verwenden
selective H1-receptor antagonist
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.
Definition
ChEBI: Gabapentin is 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. It has a role as an anticonvulsant, a calcium channel blocker, an environmental contaminant and a xenobiotic. It is functionally related to a gamma-aminobutyric acid.
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.
Trademarks
Neurontin (ParkeDavis); Neurontin (Pfizer).
Therapeutic Function
Anticonvulsant
Biologische Funktion
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.
Allgemeine Beschreibung
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.
Biologische Aktivität
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)
Nebenwirkungen
Dose-limiting adverse effects include somnolence, dizziness, ataxia, peripheral edema, and infection (22).
Nebenwirkungen
Long-Term Side Effects of Gabapentin:
- Mood changes.
- Behavioral changes.
- Depression.
- Anxiety.
- Memory loss.
- Weakened muscles.
Synthese
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.
Arzneimittelwechselwirkung
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.
Stoffwechsel
There is no evidence of gabapentin metabolism in humans. Gabapentin is eliminated unchanged solely by renal excretion.
Einzelnachweise
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

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