Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions

Abstract

When the brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) diminishes below a threshold level, the excess neuronal excitation can lead to convulsions. This imbalance in neurotransmission can be corrected by inhibition of the enzyme γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. It also has been found that raising GABA levels can antagonize the rapid elevation and release of dopamine in the nucleus accumbens, which is responsible for the reward response in addiction. Therefore, the design of new inhibitors of GABA-AT, which increases brain GABA levels, is an important approach to new treatments for epilepsy and addiction. This review summarizes findings over the last 40 or so years of mechanism-based inactivators (unreactive compounds that require the target enzyme to catalyze their conversion to the inactivating species, which inactivate the enzyme prior to their release) of GABA-AT with emphasis on their catalytic mechanisms of inactivation, presented according to organic chemical mechanism, with minimal pharmacology, except where important for activity in epilepsy and addiction. Patents, abstracts, and conference proceedings are not covered in this review. The inactivation mechanisms described here can be applied to the inactivations of a wide variety of unrelated enzymes.

Synedrella nodiflora Extract Depresses Excitatory Synaptic Transmission and Chemically-Induced In Vitro Seizures in the Rat Hippocampus

“…It is thus, also possible that SNE acted to enhance GABAergic inhibition to counterbalance the glutamateinduced hyper-excitation in this model. This may be through one of several mechanisms including, release of GABA (Rowley et al, 2012;Rassner et al, 2016), blockade of GABA reuptake (Rowley, et al, 2012;Rogawski et al, 2016), inhibition of GABA metabolizing enzymes (Treiman, 2001;Silverman, 2018) or direct interaction with GABA receptors and their channels (Sperk et al, 2004;Mareš FIGURE 6 | (A) Administration of 8-CPT (4 µM) after SNE (0.01, 0.1 and 1.0 mg/ml) on slope of fEPSPs in rat hippocampal slices after a stable baseline perfused with normal aCSF. (B) The box and whiskers graph is the total effect calculated form the AUCs of the graph above it.…”

The Taxonomy of Covalent Inhibitors

“…A comprehensive collection of mechanism-based inactivators using such strategies to target γ-aminobutyric acid amino transferase has been recently and extensively reviewed. (67)…”

Fluorimetric determination of the enantiomers of vigabatrin, an antiepileptic drug, by reversed‐phase HPLC with a novel diastereomer derivatization reagent

“…Vigabatrin has been designed as an analogue of γ ‐aminobutyric acid (GABA). The pharmacological activity of VB is promoted by the irreversible inhibition of GABA transaminase, which is responsible for the metabolism of GABA; thus, GABA levels increase in the central nervous system (Silverman, 2018). For paediatric patients, the volume of blood drawn should be as small as possible, and therefore a very small amount of plasma is available to monitor drug concentration in such patients.…”