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New Inactivators of GABA Aminotransferase for Epilepsy and Neuropathic Pain

用于治疗癫痫和神经性疼痛的新型 GABA 转氨酶灭活剂

基本信息

批准号：
10447703
负责人：
RICHARD B SILVERMAN
金额：
$ 47.85万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447703
关键词：
2 year old 4-Aminobutyrate aminotransferase Acids Active Sites Adult Adverse effects Affect Alanine Transaminase American Aminobutyric Acids Anticonvulsants Aspartate Transaminase Binding Blindness Blood - brain barrier anatomy Brain Cancer Patient Carboxylic Acids Cell Survival Chemotherapy-induced peripheral neuropathy Chronic Complex Computer Models Convulsions Crystallization Crystallography Diffusion Disease Dose Drug Kinetics Effectiveness Enzymes Epilepsy FDA approved Focal Seizure Glutamate Decarboxylase Glutamates Glutamic Acid Goals In Vitro Indiana Infantile spasms Intractable Epilepsy Modeling Modification Motor Ataxias Motor Seizures National Institute of Neurological Disorders and Stroke Neurons Neurotransmitters Normal Cell Ornithine-oxo-acid aminotransferase Paclitaxel Pain Pain management Patients Penetration Pharmaceutical Preparations Population Prodrugs Property Pyridoxal Phosphate Rattus Refractory Regulation Research Rewards Risk Schedule Sedation procedure Seizures Spinal Structure Testing Therapeutic Time Transaminases United States National Institutes of Health Universities Vigabatrin abuse liability alternative treatment analog base blood-brain barrier penetration boys chemotherapy chemotherapy induced neuropathy comparative cytotoxicity design driving force gamma-Aminobutyric Acid improved in vivo inhibitor mental state neoplastic cell novel strategies ovid painful neuropathy pediatric patients pre-clinical professor programs prophylactic relating to nervous system screening screening program side effect succinic semialdehyde

项目摘要

Project Summary/Abstract 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.

项目总结/文摘