GABA analogues

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Chapter: Medicinal Chemistry : Anticonvulsants

Anticonvulsants : GABA analogues - Synthesis and Drug Profile - a. Progabide b. Vigabatrin c. Tiagabin (Gabitril) d. Gabapentin (Gabantin, Gaba, Rejuron) - Structure, Properties, uses, Synthesis, Assay, Storage, Dosage forms, Dose | Synthesis and Drug Profile


SYNTHESIS AND DRUG PROFILE


GABA analogues

Gamma-amino butyric acid (GABA) is an inhibitory neurotransmitter. It cannot cross the blood-brain barrier (BBB). This problem is overcome by enhancing the lipid solubility by the formation of Schiff’s base of gabamide.


a. Progabide


Synthesis


Mode of action: Progabide crosses the BBB readily and is bio-transformed into its active acid metabolite. It acts as agonists for GABAA and GABAB receptors.

Properties and uses: It is a nonhygroscopic, microcrystalline, yellow powder, sparingly soluble in water. Used in simple and complex partial seizures, generalized tonic-clonic seizures, and myoclonic seizures.


b. Vigabatrin


Synthesis


Mode of action: Vigabatrin readily crosses the BBB and raises brain GABA levels by virtual of GABA transaminase enzyme inhibiton. GABA-T is responsible for the metabolism of GABA.

Properties and uses: The S (+)-enantiomer potently inhibits GABA-transaminase compared to the Renantiomer, which is almost inactive in this respect.


c. Tiagabin (Gabitril)


Synthesis


Mode of action: Tiagabin is a GABA reuptake inhibitor, which increases extracellular concentration of GABA, which in turn opens the chloride ion channels. These in turn inhibits neuronal activity by hyperpolarization and depolarization block.

Properties and uses: It exists as white crystalline powder, soluble in water and insoluble in hydrocarbons. It is proven to reduce partial seizures when given as adjunctive therapy. The most common adverse effects are dizziness, light headedness, asthma, and lack of energy.

Dose: The usual dose initially is 4 mg once daily.


d. Gabapentin (Gabantin, Gaba, Rejuron)


Mode of action: It is a lipid soluble GABA analogue. It does not bind with GABAA receptor, causes no inhi-bition on GABA reuptake and is not a GABA--T (GABA amino transferase enzyme that metabolizes GABA to succinic semialdehyde) inhibitor, thus, the mechanism of action is unknown.

Properties and uses: It is a colourless, crystalline substance, soluble in water. It has been endorsed as an effective drug for the management of neuropathic pain.

Dose: For epilesy (partial seizures with or without secondary generalization): Adult: Initially, 300 mg on the first day; 300 mg twice/day on the second day; and 300 mg thrice/day on the third day. Thereafter, the dose may increase until effective antiepileptic control is achieved. Usual maintenance range: 0.9–3.6 g daily, daily dose to be taken in three equally divided doses and maximum dosing interval of 12 h. Maximum: 4.8 g daily.

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