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

• 批准号: 10278302
• 负责人: RICHARD B SILVERMAN
• 金额: $ 50.85万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 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/10278302
• 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; 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/antagonist; 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

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/摘要 参与调节脑神经元活动的两种主要神经递质是神经递质， 氨基丁酸（GABA），最广泛分布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的浓度是由两个吡哆醛5 '-磷酸（PLP）- 依赖酶，L-谷氨酸脱羧酶（GAD），其催化L-谷氨酸转化为 GABA和GABA氨基转移酶（GABA-AT），其将GABA降解为琥珀酸半醛， 将β-酮戊二酸转化为L-谷氨酸。当GABA的浓度降低到阈值以下时 水平，惊厥的结果;提高GABA水平终止癫痫发作。当癫痫被广泛定义为任何 一种以反复惊厥性发作为特征的疾病，然后超过1%的全世界人口（包括 > 300万美国人）可以被归类为癫痫。提高GABA水平的一种方法是 穿过血脑屏障（BBB）并抑制/灭活GABA-AT的分子。这有效 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，使GABA-AT失活，用于治疗婴儿痉挛和难治性癫痫; 但它有严重的副作用。神经性疼痛，包括化疗引起的周围神经病变 （超过60%的接受化疗的癌症患者存在这个问题），影响着世界上3-17%的人。 人口目前对疼痛的治疗不足会因不良副作用而加剧，例如滥用 易受伤害、镇静和精神状态改变，这限制了治疗效用。神经性疼痛的两个特征， 已经确定的是GABA水平降低和脊髓GABA能抑制功能。的目的 建议是设计和评估我们以前成功的新的基于机制的灭活类似物 GABA-AT灭活剂提高效力并使用计算机建模阐明灭活机制 和晶体学（刘大力博士负责我们的晶体结构）作为设计的驱动力。新灭活剂 被设计用于选择性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建模。我们的新方法 一组将设计两类类似物以改善BBB渗透：被动扩散方法 涉及我们以前成功的GABA-AT灭活剂的简单前药;和主动扩散方法 其中已知与三种不同的BBB流入转运蛋白结合的分子将被并入我们的GABA- 作为前药的AT灭活剂。最后，我们新分子的有效性将由我的合作者进行测试， 博士Andrea Hohmann，用于治疗各种神经性疼痛，包括化疗引起的外周疼痛。 神经病变他们还将被送往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。