The long-term goal of this research is to design new compounds to inactivate GABA aminotransferase (GABA- AT), the enzyme that degrades the inhibitory neurotransmitter GABA, for the treatment of chemical addiction and epilepsy. Inhibition of GABA-AT, which raises GABA levels, has been shown to effectively dampen excessive neural activity without affecting basal neuronal firing. When the concentration of GABA diminishes below a threshold level in the brain, convulsions result; raising the brain GABA levels terminates the seizure. Increasing GABA levels also blocks cocaine, nicotine, methamphetamine, alcohol, and heroin addiction in rats and cocaine addiction in humans without affecting the craving for food. The neurochemical response to drugs of abuse is a sharp increase in dopamine levels in the nucleus accumbens, which activates the neurons responsible for pleasure and reward responses. The rise in dopamine and associated behaviors can be antagonized by an increase in the concentration of GABA. Vigabatrin (trade name SabrilTM), an irreversible inhibitor of GABA-AT, is currently marketed as a monotherapy for pediatric patients and as an adjunctive therapy for adults with refractory seizures. It was shown by positron emission tomography (PET) in primates that vigabatrin inhibits these cocaine-induced dopamine increases. The acceptance of vigabatrin for the treatment of both epilepsy and stimulant addiction, however, has been hampered by concerns about visual field defects (VFDs) in 25-50% of patients following chronic administration of large amounts of vigabatrin; the typical dose is 1-3 grams a day. The mechanism leading to the VFDs is not known; nonetheless, if the prevailing belief that VFDs arise from prolonged exposure to large doses of drug is correct, and if much lower doses of a drug can be used, there may be no untoward consequences. We previously designed a GABA-AT inactivator, (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), which was found to be 300 times more potent than vigabatrin in modulation of the dopamine increase induced by addictive substances and in reversal of cocaine addiction in rats as well in a model for infantile spasms. Compound 2 is currently being evaluated for safety in a clinical trial. In the last budget period we designed a new compound (17) that is 10 times more potent than 2. An aim of this proposal is to synthesize new inactivators of GABA-AT, based on 2, and study their inactivation mechanisms, including the inactivation mechanism of 17, which will be very beneficial to future inhibitor design. A third aim is to determine the structure of the new inactivators bound to GABA-AT by crystallography in collaboration with Dr. Dali Liu. A fourth aim will involve studies by collaborator Dr. Stephen Dewey on the effect of these new compounds on dopamine release in rat brains using positron emission tomography (PET) and their effect on addiction in rats and studies on their anticonvulsant activity by the Anticonvulsant Screening Program at the NIH.
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