Novel Neuroprotective Treatment for Parkinson's Disease

帕金森病的新型神经保护治疗

• 批准号: 6915939
• 负责人: Aloke K Dutta
• 金额: $ 29.42万
• 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/6915939
• 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途径的变性，导致生产胸肌，并结合刚性和震颤。尽管尚未清楚地理解PD的病因，但诸如氧化应激之类的因素现在强烈涉及多巴胺能神经元的选择性丧失。当前，尚无理想的疗法可用于减慢退化过程的进展，同时缓解与这种疾病相关的有症状异常。最近对多巴胺激动剂对PD疗法的兴趣正在增长。多巴胺激动剂除了提供较少运动并发症的PD症状缓解外，还被证明是神经保护剂。在这方面，由于多种原因，相对较新发现的多巴胺受体亚型D3已成为PD的有趣靶标。 DS优先激动剂，例如与D2选择性激动剂相比，普拉己醇可提供其他有益的神经保护作用。在此提案中，我们计划开发新型的DS选择化合物，以探索和了解该受体亚型在PD动物模型中产生反帕金森氏效应中的作用。在我们的初步研究中，我们开发了一种新型的分子模板，与D2受体相比，它对D3-表现出优先亲和力，并且与参考7-OH-DPAT相比，我们产生的分子更有效，更有选择性。在体内进行6- OHDA诱导的单侧病变大鼠的实验中，我们的铅类似物之一产生了有效的对侧旋转，其作用持续时间很长。现在，我们建议通过具有各种药理特征的全面SAR研究来扩展我们的初步发现，以开发出有效的D3优先化化合物。此外，在我们努力了解新型杂化分子与D3受体的分子相互作用时，我们将使用所选D3突变体进行定位的诱变研究，并将使用激动剂分子的全面训练集进行分子建模研究。这些实验的结果将有助于我们建立一个用于新型混合分子与D2/D3受体相互作用的药效团模型。最后，我们将测试上述实验中开发的两种最活跃的化合物是否可以在用MPTP处理的小鼠体内为多巴胺能神经元提供神经保护作用，以及该效果是否由DS-Repector介导。