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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS015703-08
Application #
3396431
Study Section
Physical Biochemistry Study Section (PB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60208
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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