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，其特征是黑质纹状体多巴胺能通路变性，导致运动迟缓并伴有僵硬和震颤。虽然PD的病因尚不清楚，但氧化应激等因素目前与多巴胺能神经元的选择性丧失密切相关。目前，还没有理想的治疗方法可以减缓变性过程的进展，同时缓解与该疾病相关的症状异常。近年来，人们对多巴胺激动剂在帕金森病治疗中的应用越来越感兴趣。多巴胺激动剂除了可以缓解帕金森病的症状，减少运动并发症外，还可以作为神经保护剂。在这方面，最近发现的多巴胺受体D3亚型由于几个原因已成为PD药物开发的有趣靶点。与d2选择性激动剂相比，ds偏好激动剂（如普拉克索）已被证明具有额外的有益神经保护作用。在本研究中，我们计划开发新的ds选择性化合物，以探索和了解该受体亚型在PD动物模型中产生抗帕金森效应的作用。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，它对D3-具有更强的亲和力，并且我们已经生成了比参考物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体内实验中，我们的一种先导类似物产生了有效的对侧旋转，作用时间长。我们现在建议扩展我们的初步发现，通过全面的SAR研究与各种药理学特征，以开发有效的d3偏好化合物。此外，为了了解我们的新型杂交分子与D3受体的分子相互作用，我们将对选定的D3突变体进行定向诱变研究，并将使用激动剂分子的综合训练集进行分子建模研究。这些实验结果将有助于我们建立新型杂交分子与D2/D3受体相互作用的药效团模型。最后，我们将在MPTP处理小鼠的体内实验中测试上述实验中开发的两种活性最高的化合物是否对多巴胺能神经元具有神经保护作用，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.