The two principal neurotransmitters involved in the regulation of brain neuronal activity are -aminobutyric acid (GABA), one of the most widely distributed inhibitory neurotransmitters, and L-glutamic acid, an excitatory neurotransmitter. The concentration of GABA is regulated by two pyridoxal 5'-phosphate (PLP)-dependent enzymes, L-glutamic acid decarboxylase (GAD), which catalyzes the conversion of L-glutamate to GABA, and GABA aminotransferase (GABA-AT), which degrades GABA to succinic semialdehyde and converts -ketoglutarate to L-glutamic acid. When the concentration of GABA diminishes below a threshold level, convulsions result; raising GABA levels terminates the seizure. When epilepsy is defined broadly as any disease characterized by recurring convulsive seizures, then over 1% of the entire world population (including >3 million Americans) can be classified as having epilepsy. One approach to raise GABA levels is with a molecule that crosses the blood-brain barrier (BBB) and inhibits/inactivates GABA-AT. This effectively dampens excessive neural activity without affecting basal neuronal firing. Vigabatrin (Sabril®) is an FDA-approved drug that inactivates GABA-AT and is used to treat infantile spasms and refractory epilepsies; however, it has serious side effects. Neuropathic pain, including chemotherapy-induced peripheral neuropathy (a problem for more than 60% of cancer patients treated with chemotherapy), affects 3-17% of the world population. Inadequate current treatments of pain are exacerbated by adverse side effects, such as abuse liability, sedation, and altered mental status, which limit treatment utility. Two features of neuropathic pain that have been identified are reduced GABA levels and spinal GABAergic inhibitory function. The objective of this proposal is to design and evaluate new mechanism-based inactivator analogs of our previously successful GABA-AT inactivators to enhance potency and elucidate inactivation mechanisms using computer modeling and crystallography (Dr. Dali Liu does our crystal structures) as the driving force for design. New inactivators are being designed for selective GABA-AT inactivation. This will require the use of comparative computer modeling with structures of compounds bound to several other aminotransferases. A new approach from our group will be the design of two classes of analogs for improved BBB penetration: a passive diffusion approach involving simple prodrugs of our previously successful GABA-AT inactivators; and an active diffusion approach in which molecules known to bind to three different BBB influx transporters will be incorporated into our GABA-AT inactivators as prodrugs. Finally, the effectiveness of our new molecules will be tested by my collaborator, Dr. Andrea Hohmann, for their effect on various neuropathic pains, including chemotherapy-induced peripheral neuropathy. They also will be sent to the NINDS Preclinical Screening Platform for Pain and to the NINDS Epilepsy Therapy Screening Program to determine their effectiveness in various in vivo epilepsy models.
|Effective start/end date||7/15/21 → 6/30/26|
- National Institute of Neurological Disorders and Stroke (1R01NS123057-01)
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