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.

项目摘要/摘要涉及调节脑神经元活性调节的两个主要神经递质是- 氨基丁酸（GABA），是分布最广泛的抑制性神经递质之一，L-谷氨酸酸之一，兴奋性神经递质。 GABA的浓度受到两个5'-磷酸吡啶多毒素（PLP） - 依赖性酶，L-谷氨酸脱羧酶（GAD），它催化L-谷氨酸转化为 GABA和GABA氨基转移酶（GABA-AT），将GABA降低到琥珀剂半甲醛和将-酮戊二酸转化为L-谷氨酸。当GABA的浓度降低到阈值以下水平，抽搐结果；提高GABA水平终止了癫痫发作。当癫痫被广泛定义为以惊厥性癫痫发作的疾病为特征 > 300万美国人）可以归类为癫痫病。提高GABA级别的一种方法是穿过血脑屏障（BBB）并抑制/失活的分子。这有效抑制过多的神经元活性，而不会影响基本的神经元放电。 Vigabatrin（Sabril®）是FDA- 批准使GABA-AT活化的药物，用于治疗婴儿痉挛和难治性癫痫；但是，它具有严重的副作用。神经性疼痛，包括化学疗法诱导的周围神经病（超过60％接受化学疗法治疗的癌症患者的问题）影响了世界的3-17％人口。当前疼痛治疗不足会因滥用等不利副作用而加剧责任，镇静和心理状况改变，这限制了治疗效用。神经性疼痛的两个特征已经鉴定出降低的GABA水平和脊柱GABA能抑制功能。这个目的建议是设计和评估我们以前成功的基于机制的新机制灭活剂类似物使用计算机建模的GABA-AT灭活因子增强和阐明灭活机制晶体学（Dali Liu博士都做我们的晶体结构）作为设计的驱动力。新的灭活因子设计用于选择性的GABA-AT灭活。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结构进行建模。我们的新方法组将是两类类似物的设计，以改善BBB渗透：一种被动扩散方法涉及我们以前成功的GABA-AT灭活因子的简单前药；和主动扩散方法其中已知与三个不同BBB影响者结合的分子将纳入我们的GABA- 在灭活因子作为前药。最后，我们的新分子的有效性将由我的合作者测试安德里亚·霍曼（Andrea Hohmann）博士对各种神经性疼痛的影响，包括化学疗法诱导的周围神经病。他们还将被发送到Ninds临床前筛查平台，以进行疼痛和Ninds 癫痫疗法筛查计划，以确定它们在各种体内癫痫模型中的有效性。