Novel substrates and inhibitors of gamma-aminobutyric acid aminotransferase (GABA-AT): Design, synthesis, biological activities, and mechanistic studies

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in brain. Low GABA levels are related to a series of neurological disorders including Parkinson's disease, Huntington's disease, Alzheimer's disease, and epilepsy. gamma-Aminobutyric acid aminotransferase (GABA-AT), the enzyme that degrades GABA, is a target for antiepilepsy drugs. Inhibition of GABA-AT results in an increase in GABA concentration and has an anticonvulsant effect.; Most reported GABA-AT inhibitors contain a hydrophilic carboxylic group, which may lead to low permeability into the blood-brain barrier (BBB). A series of potential substrates for GABA-AT were designed by replacing the carboxylic group with more lipophilic bioisosteres. The synthesized molecules were tested as GABA-AT substrates, and the tetrazole moiety was shown to be the best replacement for the carboxylic acid group. Based on the structure of the optimized tetrazole substrate and the antiepilepsy drug vigabatrin, a tetrazole derivative was designed as a potential irreversible inhibitor of the enzyme. The synthesized compound showed inhibitions to GABA-AT. Although it is not as potent as vigabatrin, it is much more lipophilic, which may provide higher permeability into the BBB and, therefore, higher in vivo activity.; Mechanistic studies of a known fluorine containing inhibitor of GABA-AT were carried out to support a proposed aromatization mechanism. The formation of a covalent adduct was confirmed. The non-enzymatic conversion of the inhibitor to gabaculine, another potent inhibitor of GABA-AT, was excluded. And the release of fluoride ions during the inactivation was observed.; Modifications of a potent conformationally rigid inhibitor of GABA-AT were made to increase the in vivo activity as well as to obtain more structural information of the enzyme active site. The synthesized analogues were tested for different characteristics. The lactam analogue showed in vivo activity as expected. The tetrazole analogue proved to be a potent inhibitor of GABA-AT. The dichloro analogue was found to be a poor inhibitor, which suggests that the chlorine atoms are too bulky for the active site of the enzyme.