Chemical Biology Approaches to Combat Parkinson's Disease and Dyskinesia

描述（由申请人提供）：L-3，4-二羟基苯丙氨酸（L-DOPA）是帕金森病（PD）的最有效治疗，但长期L-DOPA给药因运动并发症的出现而受损，即运动障碍和抗帕金森病益处的缩短（磨损）。与杜克大学的同事Marc Caron和Raul Gainetdinov博士合作，使用多巴胺耗尽的多巴胺转运蛋白敲除（DDD）小鼠模型，我们已经确定合成的芳基2-环丙胺小分子（ACP，如4-甲氧基苯基-2-环丙胺）在多巴胺转运蛋白/多巴胺缺乏（DDD）的帕金森病（PD）小鼠模型中显著对抗PD的影响。这些化合物表现出显著的抗帕金森病作用，包括从运动不能状态恢复粗大运动控制，即使在缺乏可检测水平的多巴胺的小鼠模型中也是如此。此外，我们观察到用芳基-2-环丙胺处理的DDD小鼠强烈协同地增强L-DOPA的抗帕金森病作用，将完全治疗功效所需的L-DOPA显著剂量节省至比单独的L-DOPA低>10倍的水平。初步证据表明，这些化合物通过一种新的不依赖多巴胺的机制起作用。在目的1中，我们希望在相关的6-羟基多巴胺损伤的PD大鼠模型中确定这类先导化合物的抗帕金森病活性和抗运动障碍活性。与溶剂对照相比，将评价运动不能缓解、L-DOPA治疗的剂量节省益处、抗运动障碍作用和抗帕金森病益处（ON-时间）。在目标2中，我们希望确定该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。如果这些研究是成功的，新的分子靶点抗帕金森病药物的开发可能会被发现。此外，这项工作可能会提供深入了解如何现有的目标可能会被重新定位，以有利于PD。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。

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.