Exploiting Dopamine Receptor Functional Selectivity as an Approach to Treat Parkinson's Symptoms

帕金森氏病(PD)是一种神经退行性疾病，其特征是严重的运动障碍 纹状体多巴胺(DA)输入的进行性丧失，通常使用DA前体L-多巴或DA治疗 D2受体激动剂。虽然L多巴可以改善运动障碍，但长期使用会导致运动障碍。 异常，称为L-多巴诱发的运动障碍。尽管存在这些限制，L-DOPA仍是PD的中流砥柱 治疗。不同的帕金森病动物模型表明，运动障碍与G蛋白介导的增强有关 DA受体(DAR)上的信号，这导致基因表达的变化和不受控制的神经元兴奋性。 过去十年的研究表明，DAR不仅可以通过G蛋白传递信号，还可以通过β- 阻滞素2(βARR2)支架含有启动细胞内信号的信号复合体，这些信号与G- 蛋白质。最近，我们在帕金森病模型中证明，βarr2在小鼠、大鼠或 猕猴可降低L-多巴诱发的运动障碍。这种新的方法方便了移动，同时 脱敏G蛋白信号，从而在不潜在影响其他神经递质的情况下减少运动障碍 系统。拟议研究的总体目标是为服用新型D1R和 D2RβARR偏向化合物进入临床PD试验。我们的中心假设是小分子药物 选择性地激活βARR，而不是G蛋白，D1Rs/D2Rs途径将具有抗帕金森病活性，而不是 导致运动障碍。我们有三个具体目标。AIM 1将开发βArr偏向的D1R和D2R配体 我们最近发现的线索/点击率。AIM 2将评估新合成的ARR偏向的β的体外图谱 化合物。目的3确定D1R和D2Rβ芳香族偏向化合物在动物体内的作用 帕金森病的模型。

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by severe motor deficits caused by the progressive loss of striatal dopamine (DA) input and it is commonly treated with the DA precursor L-DOPA or by DA D2 receptor (D2R) agonists. Although L-DOPA ameliorates the motor deficits, prolonged use leads to motor abnormalities, termed L-DOPA-induced dyskinesias. Despite these limitations, L-DOPA is the mainstay for PD treatment. Various animal models of PD suggest that dyskinesias are associated with enhanced G-protein mediated signaling at DA receptors (DARs) and this leads to changes in gene expression and uncontrolled neuronal excitability. Research over the past decade has shown that DARs can signal not only through G-proteins, but also also through β- arrestin2 (βarr2) scaffolds containing signaling complexes that initiate intracellular signals distinct from those of G- proteins. Recently we have demonstrated in PD models that over-expression of βarr2 in the striata of mouse, rat, or macaque reduces L-DOPA-induced dyskinesias. This novel approach facilitated locomotion and simultaneously desensitized G-protein signaling, thereby reducing the dyskinesia without potentially affecting other neurotransmitter systems. The Overall Goal of the proposed research is to provide preclinical results for taking novel D1R and D2R βarr-biased compounds into clinical PD trials. Our Central Hypothesis is that small molecule drugs that selectively activate the βarr, but not the G-protein, pathway at D1Rs/D2Rs will have anti-parkinsonian activities without inducing dyskinesias. We have three Specific Aims. Aim 1 will develop βarr-biased D1R and D2R ligands from the leads/hits we recently discovered. Aim 2 will assess the in vitro profile of the newly synthesized βarr-biased compounds. Aim 3 will determine the in vivo effects of D1R and D2R βarr-biased compounds in animal models of PD.