With the concentration of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) diminishes below a threshold level in the brain, convulsions can arise. Increasing the GABA concentration terminates the convulsion. However, since GABA does not cross the blood-brain barrier, it cannot be used as an anticonvulsant agent. An alternative approach to increase brain GABA levels has been to inhibit the enzyme that degrades GABA, namely, GABA aminotransferase (GABA-AT); the anticonvulsant drug vigabatrin is a GABA-AT inactivator used in Europe for the treatment of refractory epilepsy. The principal aims of this proposal are to design, synthesize, and determine the mechanism of inactivation of GABA-AT by a variety of new and known inactivators as well as to elucidate the structure of the enzyme or, at least, the important residues at the active site. An understanding of the detailed mechanisms of these inactivators is vital to the future design of new inactivators, not only for GABA-AT but also for the entire class of pyridoxal 5'-phosphate-dependent enzymes. The design approaches and mechanistic results will be applicable generally to enzymes that catalyze carbanion chemistry. Elucidation of the structure of GABA-AT will specifically aid in the design of new and unusual inhibitor structures. The compounds that are proposed for study are as follows: 3-amino-4,4-difluorobutanoic acid, 5-(1-amino-2-propynyl)-3- hydroxyisoxazole, (R)- and (S)-4-amino-4,5- dihydrothiophene-2-carboxylic acid, 3-fluoro-2-hydroxybenzylamine, 3,5-difluoro-4-hydroxybenzylamine, 2,4-difluoro-3-hydroxybenzylamine and the corresponding acetylenic and fluoromethyl inactivator analogs, substituted phenols as lipophilic isosteres of carboxylic acids, 4-amino-2-difluoromethyl- 2-butenoic acid, 4-amino-2-trifluromethyl-2-butenoic acid, gamma-allenyl GABA, (E)- and (Z)-4-amino-3-(fluoromethylene)butyric acids, (E)- and (Z)-3-amino-2- (fluoromethylene)propionic acids, cis- and trans-4-aminocyclopent-2-ene- 1-carboxylic acid, 3-aminocyclopent-ene-1-carboxylic acid, cis- and trans-5- amino-cyclohex-3-ene-1-carboxylic acid, and cis- and trans-2- aminocyclohex- 3-ene-1-carboxylic and the corresponding fluoroalkene analogs.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG3-BNP (02))
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Jacobs, Margaret
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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
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
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; Stevenson, S H; O'Beirne, M J et al. (1999) 2,6-Difluorophenol as a bioisostere of a carboxylic acid: bioisosteric analogues of gamma-aminobutyric acid. J Med Chem 42:329-32

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