Design and mechanism of GABA aminotransferase inactivators. Treatments for epilepsies and addictions

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.