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）是治疗帕金森病（PD）最有效的药物，但长期服用L-DOPA会出现运动并发症，即运动障碍和抗帕金森疗效缩短（逐渐消失）。在与杜克大学同事的合作中。Marc Caron和Raul Gainetdinov使用多巴胺缺失的多巴胺转运蛋白敲除（DDD）小鼠模型，我们确定了合成芳基2-环丙胺小分子（ACPs，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）小鼠PD模型中显著对抗帕金森病（PD）的影响。这些化合物表现出显著的抗帕金森效应，包括从运动障碍状态中恢复大运动控制，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DDD小鼠，可以增强左旋多巴的抗帕金森作用，达到完全治疗效果所需的左旋多巴剂量明显低于单独使用左旋多巴的10倍。初步证据表明，这些化合物是通过一种新的不依赖多巴胺的机制起作用的。在Aim 1中，我们希望在相关的6-羟多巴胺损伤大鼠PD模型中确定这类先导化合物的抗帕金森活性和抗运动障碍活性。与对照组相比，将评估运动障碍的缓解、左旋多巴治疗的剂量节约效益、抗运动障碍效果和抗帕金森病益处（ON-time）。在目标2中，我们希望确定这类先导化合物的作用模式，并确定和验证这些抗帕金森化合物的靶标。如果这些研究取得成功，可能会揭示抗帕金森病药物开发的新分子靶点。此外，这项工作可能为现有靶点如何在药理学上靶向以使PD受益提供见解。这项工作也将为使用DDD小鼠模型来协助PD药物发现工作提供支持。

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.