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：
10653918
负责人：
RICHARD B SILVERMAN
金额：
$ 47.77万
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/10653918
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 Classification Complex Computer Models Convulsions 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 Recurrence Refractory Regulation Research Rewards Risk Schedule Sedation procedure Seizures Spinal Structure Testing Therapeutic Transaminases United States National Institutes of Health Universities Vertebral column Vigabatrin abuse liability alternative treatment analog blood-brain barrier crossing blood-brain barrier penetration boys chemotherapy chemotherapy induced neuropathy comparative cytotoxicity design driving force efficacy evaluation gamma-Aminobutyric Acid improved in vivo inhibitor mental state neoplastic cell neural novel strategies ovid painful neuropathy pediatric patients pre-clinical professor programs prophylactic 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.

项目概要/摘要参与调节大脑神经元活动的两种主要神经递质是 - 氨基丁酸（GABA）是分布最广泛的抑制性神经递质之一，和L-谷氨酸，一种兴奋性神经递质，GABA 的浓度由两个 5'-磷酸吡哆醛 (PLP)- 调节。 L-谷氨酸脱羧酶（GAD），催化L-谷氨酸转化为依赖酶 GABA 和 GABA 转氨酶 (GABA-AT)，可将 GABA 降解为琥珀半醛并当 GABA 浓度降至阈值以下时，将 α-酮戊二酸转化为 L-谷氨酸。当癫痫被广义地定义为任何疾病时，GABA 水平升高会导致抽搐。其特征是反复发作惊厥性癫痫，占全世界人口的 1% 以上（包括超过 300 万美国人）可被归类为患有癫痫症，提高 GABA 水平的一种方法是使用穿过血脑屏障（BBB）并抑制/灭活 GABA-AT 的分子。抑制过度的神经活动而不影响基础神经元放电。 Vigabatrin (Sabril®) 是 FDA 批准的药物。批准的药物可灭活 GABA-AT，用于治疗婴儿痉挛症和难治性癫痫；然而，它具有严重的副作用，包括化疗引起的周围神经病变。（超过 60% 接受化疗的癌症患者面临的问题），影响了世界 3-17% 的人目前对疼痛的治疗不足会因滥用等不良副作用而加剧。责任、镇静和精神状态改变限制了神经性疼痛的两个特征。已确定降低 GABA 水平和脊髓 GABA 能抑制功能。建议是设计和评估我们之前成功的基于新机制的灭活剂类似物 GABA-AT 灭活剂可增强效力并使用计算机建模阐明灭活机制和晶体学（刘大力博士研究我们的晶体结构）作为设计的驱动力。正在设计用于选择性 GABA-AT 失活，这将需要使用比较计算机。用与几种其他氨基转移酶结合的化合物的结构进行建模是我们的一种新方法。小组将设计两类类似物以改善 BBB 渗透：被动扩散方法我们之前成功的 GABA-AT 灭活剂的简单前药以及涉及的主动扩散方法；其中已知与三种不同 BBB 流入转运蛋白结合的分子将被纳入我们的 GABA- AT 灭活剂作为前药，我们的新分子的有效性将由我的合作者进行测试。 Andrea Hohmann 博士，因其对各种神经性疼痛（包括化疗引起的外周疼痛）的作用他们还将被送往 NINDS 疼痛临床前筛查平台和 NINDS。癫痫治疗筛选计划，以确定其在各种体内癫痫模型中的有效性。