Mechanism-Based and Structure-Based Inhibitors of GABA-AT

DESCRIPTION (provided by applicant): When 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. Recently, it also was found that increasing GABA levels decreases the sharp increase in dopamine levels found to be responsible for drug addiction. However, because GABA does not cross the blood-brain barrier, it cannot be used either as an anticonvulsant agent or in the treatment of substance abuse. An alternative approach to increase brain GABA levels has been to inhibit the enzyme that degrades GABA, namely, GABA aminotransferase (GABA-AT). The specific aims of this proposal are (1) to design and synthesize new mechanism-based and structure-based inactivators and inhibitors of GABA-AT using a variety of techniques; (2) to study the mechanisms of inactivation of these compounds; (3) to use computer modeling to rationalize the activity and inactivity of our previously-studied potential inactivators of GABAAT; (4) to use computer modeling to design new inhibitors and new lead compounds based on the crystal structure coordinates of our collaborator and structure-based design software; and (5) to use the known human brain clone for mutagenesis experiments to try to determine which residues are important for inactivation. New compounds that are proposed for study include those related to the epilepsy drug vigabatrin: a series of exocyclic-methylene and exocyclic fluoromethylene analogues of 3-aminocyclopentanecarboxylate; 3-amino-4-cycloheptenecarboxylate and 3-amino-4-cyclooctenecarboxylate; 3-amino-3-(1-cyanocyclopropyl)propionate; and 4-amino-5(Z),7- octadienecarboxylate; and a series of isosteres of vigabatrin and beta-alanine-like vigabatrin analogue isosteres. Possible new carboxylate isosteres of GABA will be synthesized. A potential aromatization mechanism inactivator not related to vigabatrin is 4-amino-6,