Chemical Biology Approaches to Combat Parkinson's Disease and Dyskinesia

对抗帕金森病和运动障碍的化学生物学方法

• 批准号: 8571804
• 负责人: Dewey G McCafferty
• 金额: $ 18.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571804
• 关键词: Adverse effects; Affect; Amantadine; Amines; Antiparkinson Agents; Biochemical; Biological Assay; Biology; Bradykinesia; Brain; Bypass; Cardiovascular system; Catechols; Chemicals; Collaborations; Data; Deep Brain Stimulation; Degenerative Disorder; Development; Dopamine; Dopamine Agonists; Dose; Dyskinetic syndrome; Effectiveness; Exhibits; Future; Gold; Impaired cognition; Impulse Control Disorders; Knock-out; Knockout Mice; Lead; Lesion; Levodopa; Lewy Bodies; Light; Medical center; Mental Depression; Modeling; Molecular; Molecular Target; Monoamine Oxidase Inhibitors; Motor; Motor Manifestations; Movement; Mus; Neuraxis; Neurons; Neurotransmitters; Operative Surgical Procedures; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Planet Mars; Procedures; Rattus; Reaction; Replacement Therapy; Research Project Grants; Risk; Severities; Signal Transduction; Staging; Substantia nigra structure; Symptoms; Syndrome; Therapeutic; Time; Transferase; Treatment Efficacy; Tremor; Validation; Work; alpha synuclein; base; combat; cyclopropylamine; dopamine transporter; dopaminergic neuron; drug development; drug discovery; effective therapy; gastrointestinal; inhibitor/antagonist; insight; motor control; mouse model; neuronal circuitry; new therapeutic target; novel; programs; public health relevance; receptor binding; restoration; small molecule; standard care

DESCRIPTION (provided by applicant): L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but long- term L-DOPA administration is marred by the emergence of motor complications, namely, dyskinesia and a shortening of anti-Parkinson's benefit (wearing-OFF). In collaboration with Duke colleagues Drs. Marc Caron and Raul Gainetdinov, using a dopamine-depleted dopamine transporter knockout (DDD) mouse model, we have determined that synthetic aryl 2-cyclopropylamine small molecules (ACPs, such as 4-methoxyphenyl-2- cyclopropyl amine) significantly counter the effects of Parkinson's disease (PD) in a dopamine transporter/dopamine-deficient (DDD) mouse model of PD. These compounds exhibited marked antiparkinsonian effects including restoration of gross motor control from akinesia states, even in this mouse model that lacked detectable levels of dopamine. Furthermore, we observed that DDD mice treated with aryl-2- cyclopropylamines strongly synergistically enhanced the antiparkinsonian actions of L-DOPA, significantly dose sparing L-DOPA required for complete therapeutic efficacy to levels >10-fold lower than L-DOPA alone. Preliminary evidence suggests that these compounds work by a novel dopamine-independent mechanism. In Aim 1 we wish to determine the antiparkinsonian activity and antidyskinesia activities of lead compounds from this class in a relevant 6-hydroxydopamine-lesioned rat model of PD. Relieve from akinesia, dose-sparing benefits to L-DOPA therapy, antidyskinesia effects and antiparkinsonian benefits (ON-time) will be evaluated as compared to vehicle controls. In Aim 2 we wish to identify the mode of action of lead compounds from this class, and to identify and validate the target of these antiparkinsonian compounds. Should these studies be successful, new molecular targets for antiparkinsonian drug development may be revealed. In addition, this work may provide insight into how existing targets may be pharmacologically targeted to benefit PD. This work will also lend support to use of the DDD mouse model to assist PD drug discovery efforts.

描述（由申请人提供）：L-3,4-二羟基苯丙氨酸（L-DOPA）是治疗帕金森病（PD）最有效的方法，但长期施用L-DOPA会因运动并发症的出现而受到损害，即运动障碍和抗帕金森病益处的缩短（逐渐消失）。与杜克大学同事合作。 Marc Caron 和 Raul Gainetdinov 使用多巴胺耗尽的多巴胺转运蛋白敲除 (DDD) 小鼠模型，确定合成芳基 2-环丙胺小分子（ACP，例如 4-甲氧基苯基-2-环丙胺）可显着抵消多巴胺中帕金森病 (PD) 的影响 PD 转运蛋白/多巴胺缺陷 (DDD) 小鼠模型。这些化合物表现出显着的抗帕金森病作用，包括从运动不能状态恢复粗大运动控制，即使在缺乏可检测到的多巴胺水平的小鼠模型中也是如此。此外，我们观察到用芳基-2-环丙胺治疗的 DDD 小鼠强烈协同增强了 L-DOPA 的抗帕金森病作用，显着节省了完全治疗效果所需的 L-DOPA 剂量，其水平比单独使用 L-DOPA 低 10 倍以上。初步证据表明，这些化合物通过一种新颖的不依赖多巴胺的机制发挥作用。在目标 1 中，我们希望确定此类先导化合物在相关 6-羟基多巴胺损伤的 PD 大鼠模型中的抗帕金森病活性和抗运动障碍活性。与载体对照相比，将评估运动不能的缓解、左旋多巴治疗的剂量节省益处、抗运动障碍效果和抗帕金森病益处（ON-time）。在目标 2 中，我们希望确定此类先导化合物的作用模式，并确定和验证这些抗帕金森病化合物的靶点。如果这些研究成功，可能会揭示抗帕金森病药物开发的新分子靶点。此外，这项工作可以深入了解如何在药理学上靶向现有靶点以有益于帕金森病。这项工作还将支持使用 DDD 小鼠模型来协助 PD 药物发现工作。