Novel Neuroprotective Treatment for Parkinson's Disease

描述（由申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病，其特征为黑质纹状体多巴胺能通路的变性，导致运动迟缓的产生，并伴有强直和震颤。虽然PD的病因还不清楚，但氧化应激等因素与多巴胺能神经元的选择性丧失密切相关。目前，没有理想的疗法可用于减缓变性过程的进展，同时缓解与这种疾病相关的症状异常。近年来，多巴胺受体激动剂在PD治疗中的应用越来越受到关注。多巴胺受体激动剂，除了提供症状缓解PD与运动并发症少，也被证明是神经保护剂。在这方面，相对最近发现的多巴胺受体亚型D3已成为一个有趣的目标，用于药物开发的PD有几个原因。DS-优选激动剂例如普拉克索已显示提供超过D2-选择性激动剂所见的额外有益神经保护作用。在这个提议中，我们计划开发新的DS-选择性化合物，以探索和理解这种受体亚型在PD动物模型中产生抗帕金森病作用的作用。在我们的初步研究中，我们开发了一种新的分子模板，与D2受体相比，对D3受体表现出优先亲和力，并且我们产生了比参比7-OH-DPAT更有效和选择性的分子。在6-OHDA诱导的单侧损伤大鼠的体内实验中，我们的一种铅类似物产生了有效的对侧旋转，作用持续时间长。我们现在建议通过具有各种药理学特征的全面SAR研究来扩展我们的初步发现，以开发有效的D3偏好化合物。此外，在我们的努力，以了解我们的新的杂交分子与D3受体的分子相互作用，我们将进行定点诱变研究与选定的D3突变体，并将进行分子建模研究，使用一个全面的训练集的激动剂分子。这些实验结果将有助于我们建立一个新的杂合分子与D2/D3受体相互作用的药效团模型。最后，我们将测试在上述实验中开发的两种最具活性的化合物是否可以在用MPTP治疗的小鼠的体内实验中对多巴胺能神经元提供神经保护，以及这种作用是否由DS受体介导。

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive neurodegenerative disease which is characterized by degeneration of the nigrostriatal dopaminergic pathway resulting in production of bradykinesia in combination with rigidity and tremor. Although the etiology of PD is not clearly understood, factors such as oxidative stress are now strongly implicated in the selective loss of dopaminergic neurons. Currently, no ideal therapies are available for slowing the progression of the degeneration process and at the same time relieving symptomatic abnormalities associated with this disease. Interest in dopamine agonists in PD therapy is growing recently. Dopamine agonists, besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. In this regard, the relatively recently discovered dopamine receptor subtype D3 has become an interesting target for drug development for PD for several reasons. DS-preferring agonists e.g. pramipexole, has been shown to provide additional beneficial neuroprotective effects over that seen with D2-selective agonists. In this proposal, we plan to develop novel DS-selective compounds to explore and understand the role of this receptor subtype in producing antiparkinsonian effect in an animal model of PD. In our preliminary study, we have developed a novel molecular template exhibiting preferential affinity for the D3- compared to the D2-receptor and we have generated molecules more potent and selective than the reference 7-OH-DPAT. In in vivo experiment with 6- OHDA-induced unilaterally lesioned rats, one of our lead analogs produced potent contralateral rotations with a long duration of action. We now propose to expand on our initial findings through comprehensive SAR studies with various pharmacological characterizations to develop potent D3-preferring compounds. Furthermore, in our effort to understand molecular interaction of our novel hybrid molecules with the D3 receptor, we will carry out site-directed mutagenesis studies with the selected D3 mutants and will perform molecular modeling studies using a comprehensive training set of agonist molecules. Results from these experiments will help us to build a pharmacophore model for interaction of novel hybrid molecules with the D2/D3 receptors. Finally, we will test whether the two most active compounds developed in the above experiments can provide neuroprotection to dopaminergic neurons in vivo experiments with mice treated with MPTP and whether such an effect is mediated by the DS-receptor.