Novel Neuroprotective Treatment for Parkinson's Disease

帕金森病的新型神经保护治疗

• 批准号: 7014046
• 负责人: Aloke K Dutta
• 金额: $ 26.63万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014046
• 关键词: Parkinson' s disease; antiparkinson drugs; chemical synthesis; dopamine receptor; drug design /synthesis /production; laboratory mouse; laboratory rat; ligands; molecular dynamics; neuroprotectants; nonhuman therapy evaluation; receptor binding; site directed mutagenesis; small molecule

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.

描述（由申请人提供）：帕金森氏病（PD）是一种进行性神经退行性疾病，其特征在于黑质纹状体多巴胺能通路的退化，导致产生运动迟缓并伴有僵硬和震颤。尽管帕金森病的病因尚不清楚，但目前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，还没有理想的疗法可以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。最近，人们对多巴胺激动剂在 PD 治疗中的兴趣日益浓厚。多巴胺激动剂除了可以缓解帕金森病的症状并减少运动并发症外，还被证明可以作为神经保护剂。在这方面，由于多种原因，最近发现的多巴胺受体亚型 D3 已成为 PD 药物开发的一个有趣的靶标。 DS 偏好激动剂，例如普拉克索已被证明比 D2 选择性激动剂具有额外的有益神经保护作用。在本提案中，我们计划开发新型 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病作用的作用。在我们的初步研究中，我们开发了一种新型分子模板，与 D2- 受体相比，它对 D3- 受体表现出优先的亲和力，并且我们生成了比参考 7-OH-DPAT 更有效和更具选择性的分子。在 6-OHDA 诱导的单侧损伤大鼠的体内实验中，我们的一种先导类似物产生了有效的对侧旋转，且作用持续时间长。我们现在建议通过具有各种药理学特征的综合 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，为了了解我们的新型杂合分子与 D3 受体的分子相互作用，我们将使用选定的 D3 突变体进行定点诱变研究，并将使用一套全面的激动剂分子训练集进行分子建模研究。这些实验的结果将帮助我们建立新型杂合分子与 D2/D3 受体相互作用的药效团模型。最后，我们将在用 MPTP 治疗的小鼠体内实验中测试上述实验中开发的两种最活跃的化合物是否可以为多巴胺能神经元提供神经保护，以及这种作用是否是由 DS 受体介导的。