Chemical Biology Approaches to Combat Parkinson's Disease and Dyskinesia

描述(申请人提供)：L-3，4-二羟基苯丙氨酸(L-多巴)是治疗帕金森病(PD)最有效的药物，但长期服用L-多巴会因出现运动并发症而受到影响，即运动障碍和抗帕金森益处(疲劳)的缩短。在杜克大学同事Marc Caron博士和Raul Gainetdinov博士的合作下，我们使用多巴胺耗竭的多巴胺转运体基因敲除(DDD)小鼠模型，确定了合成的芳基2-环丙胺小分子(ACP，如4-甲氧基苯基-2-环丙胺)在多巴胺转运体/多巴胺缺乏(DDD)小鼠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症作用，包括从运动障碍状态恢复粗大运动控制，即使在这个缺乏可检测到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-环丙胺处理的DDD小鼠强烈协同增强了L-多巴的抗帕金森病作用，显著节省了L-多巴达到完全治疗效果所需的剂量，而L-多巴的剂量仅为L-多巴的10倍。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发挥作用。在目标1中，我们希望确定这类先导化合物在相关的6-羟基多巴胺损毁的帕金森病大鼠模型中的抗帕金森病活性和抗运动障碍活性。与车辆对照组相比，将评估缓解运动障碍、节省剂量的L多巴疗法、抗运动障碍效果和抗帕金森病益处(On-time)。在目标2中，我们希望鉴定这类先导化合物的作用模式，并鉴定和验证这些抗帕金森类化合物的靶标。如果这些研究成功，抗帕金森病药物开发的新分子靶点可能会被揭示。此外，这项工作可能为了解现有靶点如何通过药理学靶向使帕金森病受益提供洞察力。这项工作也将为使用DDD小鼠模型来辅助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.