GABA-transaminase inhibitor

Valproic acid (= 2-Propylpentanoic acid 2-Propylvaleric acid)] (carboxylic acid) Synthetic GABA transaminase inhibitor (cf. 4-Hydroxybenzaldehyde) [anticonvulsant, antiepileptic]... 

Palfreyman M G, Schechter P J, Buckett W R, Tell G P, and Koch Weser J. (1981) The pharmacology of GABA-transaminase inhibitors, Biochem. Pharmacol 30, 817-824... 

Disorders of GABA Vitamin B6-dependent seizures Often an absence of succinic semialdehyde dehydrogenase Hypotonia, ataxia, mental retardation in older child. Increased urine 4-OH-butyric acid. Pyridoxine (B6-dependent disorder) Inhibitors of GABA transaminase... 

Of the many drugs that have been developed which modulate GABA function, the inhibitors of GABA transaminase have been shown to be effective anticonvulsants. These are derivatives of valproic acid that not only inhibit the metabolism of GABA but may also act as antagonists of the GABA autoreceptor and thereby enhance the release of the neurotransmitter. GABA-uptake inhibitors have also been developed (for example, derivatives... 

They are different from vigabatrin (4) in that they are not inhibitors of GABA transaminase, and, in contrast to tiagabine (5), these molecules do not directly inhibit GABA reuptake (Bryans and Wustrow, 1999 Taylor, 1994). 

Vigabatrin is a new antiepileptic for use in epilepsy unresponsive to other therapy. It is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for inactivation of the neurotransmitter GABA and it has shown efficacy against partial and secondarily generalized seizures. The principal unwanted effects are psychiatric disorders, including depression and psychosis, in a small number of patients. 

It is an inhibitor of GABA transaminase which degrades GABA. It suppresses maximal electroshock and kindled seizures and is used in partial seizure with or without generalization. 

GABA is converted to succinic semialdehyde [via GABA transaminase (GABAT) + pyri-doxal phosphate] which is thence oxidized to succinic acid which is further oxidized via the TCA cycle. 4-Hydroxybenzaldehyde from Gastrodia elata (Orchidaceae), a plant with antiepileptic properties, is an inhibitor of GABAT, as is the synthetic antiepileptic valproic acid (2-propenylpropanoic acid) (Table 6.6). 

In the 2-aza-type Cope rearrangement, 4-amino-5,6-heptadienoic acid (a specific inhibitor of mammalian GABA transaminase) is prepared by the following route1121. 

A different approach led to the development of vigabatrin (Sabril). Its ability selectively and irreversibly to inhibit GABA-transaminase from metabolically inactive GABA (as a suicide inhibitor) makes it an effective agent (Fig. 12-5), particularly in complex partial seizures. 

Importantly, its precise mechanism of its anticonvulsant action is still not fully understood. However, it has been duly advocated that its administration specifically inhibits GABA-transaminase, and thereby enhancing the concentration of cerebral GABA. It has also been observed that a few other straight-chain saturated fatty acids i.e., lower fatty acids, such as propanoic acid, butyric acid, and pentanoic acid which are devoid of anticonvulsant characteristic features are relatively more potent and efficacious inhibitors of GABA-transaminase than is valproic acid. Furthermore, it has been adequately substantiated that there exists a rather stronger correlation between the anticonvulsant potency of valproate and other branched-chain fatty acids besides, their capability to minimise the prevailing concentration of cerebral aspartic acid (an amino acid). 

Bernasconi R, Maitre L, Martin P, and Raschdorf F (1982) The use of inhibitors of GABA-transaminase for the determination of GABA turnover in mouse brain regions an evaluation of ammooxyacetic acid and Gabaculine. / Neurochem. 38, 57-66. 

Loscher W. (1980) Effect of inhibitors of GABA transaminase on the synthesis, binding, uptake, and metabolism of GABA. / Neurochem 34, 1603-1608. 

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