Targeting System Xc- for the Treatment of Addiction

用于治疗成瘾的靶向系统 Xc-

基本信息

批准号：
7894918
负责人：
DAVID A BAKER
金额：
$ 66.01万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894918
关键词：
Accounting Acetylcysteine Amino Acids Biological Availability Blood Blood - brain barrier anatomy Brain Bypass Chemicals Clinical Clinical Research Cocaine Cocaine Dependence Consumption Cues Cysteine Cystine Data Dopamine Dose Drug Kinetics Environment Exhibits Exposure to Extinction (Psychology)Figs - dietary Glutamates Goals Hepatic Human Illicit Drugs In Vitro Injection of therapeutic agent Left Ligands Link Liver Metabolism Metabotropic Glutamate Receptors Microdialysis Modeling Nucleus Accumbens Pathway interactions Pattern Permeability Pharmaceutical Preparations Pharmacotherapy Pre-Clinical Model Prodrugs Rattus Rodent Rodent Model Screening procedure Series Signal Transduction Societies Solid Stimulus Stress Synapses Synaptic Transmission System Techniques Testing Therapeutic Translating addiction antiporter base brain cell clinical efficacy cocaine use cost craving design drug craving drug of abuse drug relapse effective therapy extracellular fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether improved in vitro Assay in vivo neurotransmission new therapeutic target novel passive transport pre-clinical receptor relating to nervous system research study

项目摘要

Addiction to cocaine and other illicit drugs is estimated to cost our society $181 billion which equates to $603 per U.S. citizen. The cost of addiction can be dramatically lowered through the use of treatments; unfortunately, many drugs of abuse, including cocaine, lack a single approved pharmacotherapy. Addiction to psychomotor stimulants, such as cocaine, is marked by a transition in drug consumption from a casual, recreational style of use to a more compulsive, excessive pattern that arises as a result of drug-induced changes in brain functioning. In order to develop effective treatments, it will likely be necessary to identify and target altered brain functioning underlying addiction. Towards this end, drug-induced changes in glutamate release from cystine-glutamate antiporters have been linked to pathological alterations in neural transmission and normalizing cystine-glutamate exchange blocks compulsive drug-seeking in preclinical models. Further, small-scale clinical studies using acetylcysteine to target cystine-glutamate exchange have shown modest efficacy including reduced drug craving and cocaine use. The efficacy of N-acetyl cysteine is limited due to extensive metabolism in the liver and poor passive transport into the brain. As a result, the present proposal seeks to develop novel chemical entities that are more potent and effective in targeting cystine-glutamate exchange in the brain. Aim 1 will involve the design of 32-40 compounds. Aim 2 will utilize in vitro and in vivo screening techniques to determine which compounds are most effective and potent in targeting cystine-glutamate exchange. Specifically, we will use pure glial cortical cultures to determine the capacity of brain cells to utilize the novel ligands to target cystine-glutamate exchange. Next, we will screen the most promising compounds in vivo by assessing the capacity of these ligands to bypass hepatic metabolism, enter into the brain, and target cystine-glutamate antiporters. Aim 3 will determine the potency and efficacy of these novel compounds in blocking cocaineprimed, stress-primed, and cocaine-paired cue primed reinstatement of cocaine-seeking in preclinical models of compulsive drug seeking. Collectively, these experiments have the potential to identify cystine-glutamate antiporters as a novel target in the treatment of addiction and to generate a series of compounds that may ultimately be effective in treating cocaine addiction.

估计对可卡因和其他非法药物的成瘾将使我们的社会损失1810亿美元每位美国公民等于603美元。成瘾的成本可以大大降低通过使用治疗；不幸的是，包括可卡因在内的许多滥用药物都缺乏单批准的药物治疗。对可卡因等精神运动兴奋剂的成瘾是以毒品消费从休闲，休闲风格的过渡到更多的标志由于药物诱导的大脑变化而产生的强迫性，过度模式功能。为了开发有效的治疗，可能有必要确定目标改变了大脑功能的基本成瘾。为此，毒品引起的胱氨酸谷氨酸抗植物的谷氨酸释放的变化已与神经传播和标准化胱氨酸 - 谷氨酸交换的病理改变阻止临床前模型中的强迫毒品寻求药物。此外，小型临床研究使用乙酰半胱氨酸靶向胱氨酸 - 谷氨酸交换已显示出适中的功效包括减少渴望和可卡因的使用。 N-乙酰半胱氨酸的功效有限由于肝脏中的新陈代谢以及向大脑的被动运输不良。因此，本提案旨在开发更有效的新型化学实体，并且有效靶向大脑中的胱氨酸 - 谷氨酸交换。 AIM 1将涉及设计 32-40种化合物。 AIM 2将利用体外和体内筛选技术确定哪些化合物在靶向胱氨酸 - 谷氨酸方面最有效和有效交换。具体而言，我们将使用纯粹的神经胶质皮质培养物来确定脑细胞利用新型配体靶向胱氨酸 - 谷氨酸交换。接下来，我们会的通过评估这些配体的能力来筛选体内最有希望的化合物绕过肝新陈代谢，进入大脑，靶向胱氨酸 - 谷氨酸抗植物。目的 3将确定这些新型化合物在阻断可卡因的效力和功效，压力染色和可卡因培养的提示在恢复可卡因的恢复原始强迫药的临床前模型。总的来说，这些实验具有潜力鉴定胱氨酸 - 谷氨酸抗植物作为治疗的新目标成瘾并产生一系列可能有效治疗的化合物可卡因成瘾。