Novel Neuroprotective Treatment for Parkinson's Disease

描述(申请人提供)：帕金森病(PD)是一种以黑质纹状体多巴胺能通路退化为特征的进行性神经退行性疾病。帕金森病的主要临床特征包括静止性震颤、僵硬、启动运动困难和姿势不稳定。目前，还没有理想的治疗方法来减缓退变过程的进展，同时缓解与这种疾病相关的症状异常。虽然帕金森病的发病机制尚不清楚，但氧化应激和线粒体功能障碍都与多巴胺细胞死亡密切相关，这些都与谷胱甘肽丢失和游离铁浓度增加有关。越来越明显的是，对于像帕金森病这样的复杂疾病，只针对一个靶点的药物只能部分解决疾病的治疗需求。这项建议的总体目标是开发多功能治疗剂，不仅可用于对症治疗，还可通过促进DA神经元的存活而用作疾病改良剂。多巴胺D3首选的激动剂除了能缓解帕金森病的症状，减少运动并发症外，还被证明是神经保护剂。在两个不同的动物模型研究中，D3更喜欢从我们的新的杂交模板中衍生的化合物D-264被证明具有神经保护作用。我们的研究表明，D-264与D3受体的相互作用以及它的其他性质，如抗氧化剂，可能是其神经保护作用的原因。在另一项初步发展中，已经开发出具有螯合铁能力的独特的多功能多巴胺D2/D3激动剂化合物。这些分子不仅有望缓解帕金森病患者的运动功能障碍，而且还有可能通过与铁的螯合来减轻帕金森病大脑中的氧化应激，铁与该病的发病机制有关。初步研究表明，这些化合物具有跨越血脑屏障的能力，在细胞培养和体内MPTP小鼠模型实验中，其中一个铅分子显示出神经保护作用。我们现在建议扩大基于混合D-264相关类似物的药物开发研究，以改善药代动力学性质，提高生物利用度，并开展多价铁结合D2/D3激动剂的扩展构效关系研究。从这两个系列化合物中挑选出的分子将在帕金森病动物模型中进行评估，以确定特异性和有效性。来自这些研究的有希望的线索接下来将在神经保护研究中进行评估，其中包括急性神经毒物MPTP和慢性DOX诱导的多巴胺能谷胱甘肽耗竭转基因小鼠模型。

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. The cardinal clinical features of PD include resting tremor, rigidity, difficulty initiating movement, and postural instability. 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. Although the pathogenesis of PD is poorly understood both oxidative stress and mitochondrial dysfunction resulting from loss of glutathione with increased concentration of free iron have been strongly implicated in dopamine cell death. It is increasingly evident that for a complex disease such as PD, a drug targeting only one target site will only partially address the therapeutic need of the disease. The overall goal in this proposal is to develop multifunctional therapeutic agents which will be useful not only in symptomatic treatment but also could be used as disease-modifying agents by promoting survival of DA neurons. Dopamine D3 preferring agonists besides providing symptomatic relief in PD with less motor complications, have also been shown to act as neuroprotective agents. A D3 preferring compound D-264 derived from our novel hybrid template was shown to be neuroprotective in two different animal models studies. Our studies demonstrated that interaction of D-264 with the D3 receptor along with its other properties e.g. antioxidant, might be responsible for its neuroprotection property. In another preliminary development, unique multifunctional dopamine D2/D3 agonist compounds with a capacity to chelate iron have been developed. Such molecules are not only expected to relieve motor dysfunction in PD but also will have the potential to reduce oxidative stress in the PD brain by chelating with iron which has been implicated in the pathogenesis of the disease. Initial studies indicate facile blood-brain-barrier crossing ability of these compounds, and in cell culture and in vivo MPTP mouse model experiments one of the lead molecules indicated neuroprotection property. We now propose to expand drug development studies based on hybrid D-264 related analogues to improve pharmacokinetic properties to increase bioavailability and to carry out expanded structure activity relationship studies on multivalent iron binding D2/D3 agonists. Selected molecules from these two series of compounds will be evaluated in PD animal models to determine specificity and efficacy. Promising leads from these studies will next be evaluated in neuroprotection studies which include both acute neurotoxicant MPTP and chronic dox-inducible dopaminergic glutathione depletion transgenic mouse models.