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: 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
• 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

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.

项目摘要/摘要 参与调节脑神经元活动的两种主要神经递质是- 氨基丁酸是分布最广泛的抑制性神经递质之一，L-谷氨酸， 一种兴奋性神经递质。GABA的浓度受两种吡哆醛5‘-磷酸(PLP)- 依赖酶L-谷氨酸脱羧酶(GAD)，催化L-谷氨酸转化为 GABA，和GABA转氨酶(GABA-AT)，将GABA降解为琥珀酸半醛和 将-酮戊二酸转化为L-谷氨酸。当GABA浓度降至某一阈值以下时 水平，导致抽搐；提高GABA水平可终止癫痫。当癫痫被广义地定义为 以反复惊厥发作为特征的疾病，占世界总人口的1%以上(包括 300万美国人)可以被归类为癫痫。提高GABA水平的一种方法是通过 穿过血脑屏障(BBB)并抑制/失活GABA-AT的分子。这有效地 抑制过度的神经活动，而不影响基础神经元的放电。Vigabatrin(Sabril®)是FDA- 被批准的使GABA-AT失活的药物，用于治疗婴儿痉挛和难治性癫痫； 然而，它有严重的副作用。神经病理性疼痛，包括化疗引起的周围神经病 (60%以上接受化疗的癌症患者的问题)，影响着世界上3%-17%的人 人口。目前对疼痛的不充分治疗因不良副作用而加剧，如滥用 易感性、镇静剂和改变的精神状态，限制了治疗的效用。神经病理性疼痛的两个特征 已确定的是GABA水平降低和脊髓GABA能抑制功能。这样做的目的是 建议是设计和评估我们以前成功的基于机制的新的灭活剂类似物 用计算机模拟增强GABA-AT灭活剂的效力并阐明灭活机制 和结晶学(刘达利博士研究我们的晶体结构)作为设计的驱动力。新型灭活剂 是为选择性GABA-AT失活而设计的。这将需要使用比较计算机 用与其他几种氨基转移酶结合的化合物的结构进行建模。我们的一种新方法 小组将设计两类类似物来改善血脑屏障的渗透率：被动扩散法 涉及我们之前成功的GABA-AT失活剂的简单前药；以及主动扩散方法 其中已知与三种不同的BBB内流转运蛋白结合的分子将被整合到我们的GABA- 把灭活剂当做前药。最后，我们新分子的有效性将由我的合作者进行测试， Andrea Hohmann博士，因其对各种神经病理性疼痛的效果，包括化疗引起的外周疼痛 神经病。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。