权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

New Inactivators of GABA Aminotransferase for Addiction and Epilepsy

用于治疗成瘾和癫痫的新型 GABA 转氨酶灭活剂

基本信息

批准号：
9910372
负责人：
RICHARD B SILVERMAN
金额：
$ 48.14万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910372
关键词：
2 year old 4-Aminobutyrate aminotransferase Acids Adult Affect Alanine Transaminase Alcohol dependence Alcohols Anticonvulsants Aspartate Transaminase Attenuated Behavior Behavioral Belief Binding Blindness Brain Brain region Budgets Chemicals Chicago Chronic Clinical Trials Cocaine Cocaine Dependence Collaborations Complex Computer Models Convulsions Crystallization Crystallography Dopamine Dopamine Receptor Dose Drug Kinetics Enzymes Epilepsy Exposure to FDA approved Family Family suidae Focal Seizure Future Glutamate Decarboxylase Goals Heroin Dependence Human Image In Vitro Infantile spasms Institutes Laboratories Measures Medical Research Methamphetamine Methamphetamine dependence Modeling Molecular Mus Names National Institute of Neurological Disorders and Stroke Neurons Neurotransmitters New York Nicotine Nicotine Dependence Nucleus Accumbens Ornithine-oxo-acid aminotransferase Patients Pharmaceutical Preparations Phase I Clinical Trials Positron-Emission Tomography Primates Psychostimulant dependence Pyridoxal Phosphate Raclopride Radioactive Rattus Refractory Research Research Contracts Resolution Rewards Risk Rodent Safety Scotoma Seizures Structure System Testing Time Transaminases United States National Institutes of Health Universities Vigabatrin Work addiction alternative treatment analog base conditioned place preference design drug of abuse fluorodeoxyglucose food craving gamma-Aminobutyric Acid glucose metabolism improved in vivo inhibitor/antagonist medical schools microPET mouse model neurochemistry neuroimaging pediatric patients pleasure preference public health relevance relating to nervous system response screening program

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to design new compounds to inactivate GABA aminotransferase (GABA- AT), the enzyme that degrades the inhibitory neurotransmitter GABA, for the treatment of chemical addiction and epilepsy. Inhibition of GABA-AT, which raises GABA levels, has been shown to effectively dampen excessive neural activity without affecting basal neuronal firing. When the concentration of GABA diminishes below a threshold level in the brain, convulsions result; raising the brain GABA levels terminates the seizure. Increasing GABA levels also blocks cocaine, nicotine, methamphetamine, alcohol, and heroin addiction in rats and cocaine addiction in humans without affecting the craving for food. The neurochemical response to drugs of abuse is a sharp increase in dopamine levels in the nucleus accumbens, which activates the neurons responsible for pleasure and reward responses. The rise in dopamine and associated behaviors can be antagonized by an increase in the concentration of GABA. Vigabatrin (trade name SabrilTM), an irreversible inhibitor of GABA-AT, is currently marketed as a monotherapy for pediatric patients and as an adjunctive therapy for adults with refractory seizures. It was shown by positron emission tomography (PET) in primates that vigabatrin inhibits these cocaine-induced dopamine increases. The acceptance of vigabatrin for the treatment of both epilepsy and stimulant addiction, however, has been hampered by concerns about visual field defects (VFDs) in 25-50% of patients following chronic administration of large amounts of vigabatrin; the typical dose is 1-3 grams a day. The mechanism leading to the VFDs is not known; nonetheless, if the prevailing belief that VFDs arise from prolonged exposure to large doses of drug is correct, and if much lower doses of a drug can be used, there may be no untoward consequences. We previously designed a GABA-AT inactivator, (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), which was found to be 300 times more potent than vigabatrin in modulation of the dopamine increase induced by addictive substances and in reversal of cocaine addiction in rats as well in a model for infantile spasms. Compound 2 is currently being evaluated for safety in a clinical trial. In the last budget period we designed a new compound (17) that is 10 times more potent than 2. An aim of this proposal is to synthesize new inactivators of GABA-AT, based on 2, and study their inactivation mechanisms, including the inactivation mechanism of 17, which will be very beneficial to future inhibitor design. A third aim is to determine the structure of the new inactivators bound to GABA-AT by crystallography in collaboration with Dr. Dali Liu. A fourth aim will involve studies by collaborator Dr. Stephen Dewey on the effect of these new compounds on dopamine release in rat brains using positron emission tomography (PET) and their effect on addiction in rats and studies on their anticonvulsant activity by the Anticonvulsant Screening Program at the NIH.

描述（由申请人提供）：本研究的长期目标是设计新的化合物来抑制GABA氨基转移酶（GABA-AT），该酶降解抑制性神经递质GABA，用于治疗化学成瘾和癫痫。抑制GABA-AT，提高GABA水平，已被证明可以有效地抑制过度的神经活动，而不影响基础神经元放电。当GABA的浓度降低到大脑中的阈值水平以下时，就会导致惊厥;提高大脑GABA水平会终止癫痫发作。增加GABA水平还可以阻断大鼠的可卡因、尼古丁、甲基苯丙胺、酒精和海洛因成瘾以及人类的可卡因成瘾，而不会影响对食物的渴望。对滥用药物的神经化学反应是脑桥核中多巴胺水平的急剧增加，这激活了负责快乐和奖励反应的神经元。多巴胺和相关行为的增加可以通过GABA浓度的增加来拮抗。氨己烯酸（商品名SabrilTM）是一种不可逆的GABA-AT抑制剂，目前作为儿科患者的单药治疗和成人难治性癫痫发作的预防治疗上市。正电子发射断层扫描（PET）显示，在灵长类动物中，氨己烯酸抑制可卡因诱导的多巴胺增加。然而，氨己烯酸用于治疗癫痫和兴奋剂成瘾两者的接受受到了对在长期施用大量氨己烯酸后25-50%的患者中的视野缺陷（VFD）的担忧的阻碍;典型剂量是每天1-3克。导致VFD的机制尚不清楚;尽管如此，如果普遍认为VFD是由长期暴露于大剂量药物引起的是正确的，并且如果可以使用低得多的药物剂量，则可能没有不良后果。我们先前设计了一种GABA-AT灭活剂，（1 S，3S）-3-氨基-4-二氟亚甲基-1-环戊酸（2），发现其在调节成瘾物质诱导的多巴胺增加和逆转大鼠以及婴儿痉挛模型中的可卡因成瘾方面的效力是氨己烯酸的300倍。目前正在临床试验中评估化合物2的安全性。在上一个预算期间，我们设计了一种新的化合物（17），其效力是2的10倍。本研究的目的是以2为基础合成新的GABA-AT失活剂，并研究其失活机理，包括17的失活机理，这将对今后的抑制剂设计非常有益。第三个目标是与刘大力博士合作，通过晶体学确定与GABA-AT结合的新灭活剂的结构。第四个目标将涉及合作者Stephen Dewey博士使用正电子发射断层扫描（PET）研究这些新化合物对大鼠大脑中多巴胺释放的影响及其对大鼠成瘾的影响，以及NIH抗惊厥筛选计划对其抗惊厥活性的研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction.

DOI：
10.1021/jacs.7b10965
发表时间：
2018-02-14
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Juncosa JI;Takaya K;Le HV;Moschitto MJ;Weerawarna PM;Mascarenhas R;Liu D;Dewey SL;Silverman RB
通讯作者：
Silverman RB

Ornithine aminotransferase versus GABA aminotransferase: implications for the design of new anticancer drugs.