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

利用多巴胺受体功能选择性作为治疗帕金森症状的方法

• 批准号: 9289668
• 负责人: Marc G. Caron
• 金额: $ 66.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289668
• 关键词: Acute; Adverse effects; Affect; Agonist; Animal Model; Animals; Antiparkinson Agents; Antipsychotic Agents; Behavior; Biochemical; Biological Assay; Chronic; Clinical; Clinical Trials; Complex; Corpus striatum structure; Cyclic AMP; Data; Disease model; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dyskinetic syndrome; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Gene Expression; Goals; Gold; In Vitro; Incidence; Knockout Mice; L-DOPA induced dyskinesia; Lead; Levodopa; Ligands; Locomotion; Macaca; Mediating; Midbrain structure; Modeling; Monitor; Motor; Movement Disorders; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurotransmitters; Outcome; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Production; Rattus; Receptor Signaling; Reporting; Research; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Symptoms; Synthesis Chemistry; System; Testing; Therapeutic; aripiprazole; base; desensitization; dopaminergic neuron; experience; experimental study; in vivo; locomotor deficit; motor deficit; motor disorder; motor symptom; mouse model; neuronal excitability; novel; novel strategies; overexpression; pre-clinical; preclinical study; prevent; receptor; response; scaffold; small molecule; success

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.

帕金森病 (PD) 是一种神经退行性疾病，其特征是由帕金森病引起的严重运动缺陷 纹状体多巴胺 (DA) 输入逐渐丧失，通常用 DA 前体 L-DOPA 或 DA 治疗 D2 受体 (D2R) 激动剂虽然可以改善运动缺陷，但长期使用会导致运动缺陷。 尽管有这些限制，L-DOPA 仍是 PD 的主要治疗手段。 PD 的各种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) 信号传导，这会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 蛋白发出信号，还可以通过 β-蛋白发出信号。 抑制蛋白 2 (βarr2) 支架含有信号复合物，可启动与 G- 不同的细胞内信号 最近，我们在 PD 模型中证明，βarr2 在小鼠、大鼠或小鼠的纹状体中过度表达。 猕猴减少了左旋多巴引起的运动障碍，同时促进了运动。 使 G 蛋白信号传导脱敏，从而减少运动障碍，而不会影响其他神经递质 拟议研究的总体目标是为服用新型 D1R 和系统提供临床前结果。 D2R βarr 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 选择性激活 D1Rs/D2Rs 处的 βarr，而不是 G 蛋白，将具有抗帕金森病活性，而无需 我们有三个具体目标 1 将开发 βarr 偏向的 D1R 和 D2R 配体。 我们最近发现的先导/命中目标 2 将评估新合成的 βarr 偏向的体外特征。 目标 3 将确定 D1R 和 D2R βarr 偏向化合物在动物体内的作用。 PD 模型。