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.
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