Beta-Arrestin-Biased Agonism at the D1 Receptor as a Novel Approach to Levodopa-Induced Dyskinesias in Advanced Parkinson's Disease

D1 受体的 β-抑制蛋白偏向激动是治疗晚期帕金森病中左旋多巴引起的运动障碍的新方法

• 批准号: 10022079
• 负责人: Michael Louis Martini
• 金额: $ 4.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2021-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022079
• 关键词: Adverse effects; Age; Agonist; Animals; Antiparkinson Agents; Arr2; Arrestins; Artificial Membranes; Behavior; Binding; Binding Sites; Biological Assay; Carbidopa; Catechols; Cell Membrane Permeability; Central Nervous System Diseases; Chemicals; Clinical; Complex; Computer Analysis; Corpus striatum structure; DRD2 gene; Data; Degenerative Disorder; Development; Disease model; Docking; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dyskinetic syndrome; Elements; Free Energy; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gait; Genetic; Homology Modeling; In Vitro; Individual; Knowledge; L-DOPA induced dyskinesia; Lead; Levodopa; Ligands; Light; Locomotion; Mediating; Medical; Midbrain structure; Modality; Modeling; Modernization; Molecular; Motor; Mutagenesis; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pharmacology; Play; Population; Posture; Prevalence; Process; Property; Quality of life; Receptor Signaling; Reporting; Research; Rest Tremor; Rodent; Rodent Model; Role; Route; Series; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Substantia nigra structure; Symptoms; Testing; Therapeutic; Therapeutic Uses; Validation; advanced disease; aging population; analog; base; beta-arrestin; blood-brain barrier penetration; blood-brain barrier permeabilization; desensitization; design; dopaminergic neuron; experience; experimental study; improved; in silico; in vivo; insight; molecular dynamics; motor deficit; motor function improvement; neurobiological mechanism; nigrostriatal pathway; nonhuman primate; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; patient population; prevent; protein activation; receptor; receptor binding; recruit; response; scaffold; side effect; small molecule; societal costs; standard care; standard of care; success; tool

PROJECT SUMMARY Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the world with a prevalence estimated to be approximately 1% in people over age 60, making it an increasingly important medical problem in our aging population. Levodopa is the current standard of care for PD and functions by increasing levels of dopamine centrally in the dopamine-depleted nigrostriatal pathway. Levodopa, however, is not a viable agent for long-term therapeutic use as undesirable side effects, notably motor fluctuations termed Levodopa-induced dyskinesias (LIDs), are commonly reported. LIDs are estimated to occur in over 50% of PD patients after 5 to 10 years of treatment and disproportionately impact older PD patients at more advanced disease stages by substantially limiting the therapeutic options for this population subset. Recent research has elucidated that, in addition to G protein signaling, dopamine receptors can also signal through a distinct b-arrestin2 (b-arr2)-dependent pathway. This pathway is important in regulating downstream responses at the Dopamine 1 Receptor (D1R) and plays a significant role in converting dopamine signaling into motor function. Previous studies showed that genetic modulation of b-arr2 signaling at D1R in rodent and non-human primate PD models improved motor functioning, while preventing LIDs. The differential activation of these distinct downstream signaling pathways by a ligand is termed “functional selectivity” or “biased agonism”, and to date, the 𝛽-arr2 signaling pathway at D1R has not been pharmacologically targeted in a functionally selective manner to potentially reduce the adverse effects associated with Levodopa. To accomplish this, Aim 1 proposes the synthesis and characterization of new D1R ligands by systematically modifying a previously identified D1R-selective, non-catechol lead compound. Ligands will be profiled for functional selectivity using three assays that detect their relative potencies at activating G protein and b-arr2 signaling at D1R. The blood-brain barrier permeability of each ligand will be assessed using a validated artificial membrane assay. In Aim 2, in silico docking studies, molecular dynamics-based free- energy calculations, and model validation experiments utilizing previously synthesized analogues with diverse functional selectivity profiles will be performed to identify D1R structural elements that are important for 𝜷-arr2 bias. These results will provide critical structural information to help deduce a structural mechanism for 𝛽-arr2 recruitment at D1R and a structure-functional selectivity relationship (SFSR) that will inform further scaffold optimization into a potent, 𝛽-arr2-biased compound. Findings from this project will greatly advance knowledge in the field by providing chemical tools that will enable the study of how biased signaling occurs at D1R and how molecular pathways downstream of this receptor contribute to PD and LID pathophysiologies. The insights gained from such studies will provide important clues guiding novel therapeutic approaches to this challenging, unsolved medical problem. !

项目概要 帕金森病（PD）是世界上第二常见的神经退行性疾病， 据估计，60 岁以上人群的患病率约为 1%，这使其成为一个日益重要的因素 左旋多巴是我们老龄化人口中的医疗问题，是帕金森病和功能障碍的当前护理标准。 然而，多巴胺耗尽的黑质纹状体通路中的多巴胺水平增加。 由于不良副作用（称为显着的运动波动），不是长期治疗用途的可行药物 据估计，超过 50% 的人会发生左旋多巴诱发的运动障碍 (LID)。 PD 患者经过 5 至 10 年的治疗，对老年 PD 患者的影响更大 通过大大限制该人群子集的治疗选择来达到晚期疾病阶段。 最近的研究表明，除了 G 蛋白信号传导外，多巴胺受体还可以 通过独特的 b-arrestin2 (b-arr2) 依赖性途径发出信号，该途径对于调节非常重要。 多巴胺 1 受体 (D1R) 的下游反应，在多巴胺转化中发挥重要作用 先前的研究表明，D1R 上的 b-arr2 信号传导的基因调节。 啮齿类动物和非人类灵长类动物 PD 模型改善了运动功能，同时预防 LID。 通过配体激活这些不同的下游信号传导途径被称为“功能选择性”或 “偏向激动”，迄今为止，D1R 处的𝛽-arr2 信号通路尚未成为药理学目标 以功能选择性的方式潜在地减少与左旋多巴相关的不良反应。 为了实现这一目标，目标 1 提出通过以下方法合成和表征新的 D1R 配体： 配体系统地修饰先前鉴定的 D1R 选择性非儿茶酚先导化合物。 将使用三种检测方法来检测其激活 G 的相对效力，以分析其功能选择性 D1R 处的蛋白质和 b-arr2 信号传导将使用评估每个配体的血脑屏障渗透性。 在目标 2 中，基于分子动力学的自由对接研究。 利用先前合成的类似物进行能量计算和模型验证实验 将进行不同的功能选择性分析来识别 D1R 结构元件 对于 𝜷-arr2 偏差很重要。这些结果将提供关键的结构信息，以帮助推断结构。 在 D1R 处招募 𝛽-arr2 的机制以及结构-功能选择性关系 (SFSR) 将 为进一步将支架优化为有效的、偏向 𝛽-arr2 的化合物提供信息。 该项目的研究结果将通过提供化学工具来极大地推进该领域的知识 将能够研究 D1R 上的偏向信号传导如何发生以及该信号下游的分子途径如何 受体对 PD 和 LID 病理生理学的贡献将提供从此类研究中获得的见解。 指导新的治疗方法解决这一具有挑战性的、尚未解决的医学问题的重要线索。 ！