Based on the mechanism of action of gamma-aminobutyric acid transaminase, numerous specific irreversible inactivators have been designed and some synthesized. For those compounds which exhibit irreversible inactivation, the mechanism of the inactivation will be studied and the active site residues which are labeled will be determined. The mechanism of inhibition of some known GABA transaminase inhibitors also will be investigated. Compounds which are potent inactivators of GABA transaminase will be tested for anticonvulsant activity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Physical Biochemistry Study Section (PB)
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Wang, Zhiyong; Silverman, Richard B (2004) Synthesis of cyclopropane isosteres of the antiepilepsy drug vigabatrin and evaluation of their inhibition of GABA aminotransferase. J Enzyme Inhib Med Chem 19:293-301
Storici, Paola; De Biase, Daniela; Bossa, Francesco et al. (2004) Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin. J Biol Chem 279:363-73
Pan, Yue; Calvert, Kristi; Silverman, Richard B (2004) Conformationally-restricted vigabatrin analogs as irreversible and reversible inhibitors of gamma-aminobutyric acid aminotransferase. Bioorg Med Chem 12:5719-25
Fu, Mengmeng; Silverman, Richard B (2004) Inactivation of gamma-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2-furancarboxylic acid does not proceed by the expected aromatization mechanism. Bioorg Med Chem Lett 14:203-6
Pan, Yue; Qiu, Jian; Silverman, Richard B (2003) Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent gamma-aminobutyric acid aminotransferase inhibitor. J Med Chem 46:5292-3
Choi, Sun; Silverman, Richard B (2002) Inactivation and inhibition of gamma-aminobutyric acid aminotransferase by conformationally restricted vigabatrin analogues. J Med Chem 45:4531-9
Choi, Sun; Storici, Paola; Schirmer, Tilman et al. (2002) Design of a conformationally restricted analogue of the antiepilepsy drug Vigabatrin that directs its mechanism of inactivation of gamma-aminobutyric acid aminotransferase. J Am Chem Soc 124:1620-4
Koo, Y K; Nandi, D; Silverman, R B (2000) The multiple active enzyme species of gamma-aminobutyric acid aminotransferase are not isozymes. Arch Biochem Biophys 374:248-54
Qiu, J; Silverman, R B (2000) A new class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of gamma-aminobutyric acid aminotransferase. J Med Chem 43:706-20
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