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. !

项目摘要 帕金森氏病（PD）是世界上第二常见的神经退行性疾病 患病率估计在60岁以上的人中约为1％，使其变得越来越重要 我们老龄化的医疗问题。 Levodopa是当前对PD的护理标准和功能 多巴胺在耗尽的黑质纹状体途径中集中升高。但是，左旋多巴是 这不是长期治疗用作不良副作用的可行药物，特别是称为运动波动 左旋多巴引起的运动障碍（盖）通常报道。盖子估计发生在超过50％ 5至10年治疗后的PD患者，并不成比例地影响年龄较大的PD患者 高级疾病阶段通过实质上限制了该人群子集的治疗选择。 最近的研究阐明了，除了G蛋白信号传导外，多巴胺受体也可以 通过独特的B-arrestin2（B-arr2）依赖性途径发出信号。该途径对于调节很重要 多巴胺1受体（D1R）的下游反应，在转化多巴胺中起重要作用 发出发出电动机功能的信号。先前的研究表明，在D1R中，B-arr2信号的遗传调节 啮齿动物和非人类灵长类动物PD模型改善了运动功能，同时预防盖子。差异 通过配体激活这些独特的下游信号通路，称为“功能选择性”或 “偏见的激动剂”，迄今为止，D1R处的𝛽-arr2信号通路尚未被药理靶向 以功能性选择性的方式有可能减少与左旋多巴相关的不利影响。 为此，AIM 1提案通过 系统地修改先前鉴定的D1R选择性非catechol铅化合物。配体 将使用三个检测其相对电位的激活G的测定法进行功能选择性。 D1R处的蛋白质和B-arr2信号传导。每种配体的血脑屏障渗透性将使用 经过验证的人造膜测定法。在AIM 2中，在计算机对接研究中，基于分子动力学的自由 - 能源计算以及模型验证实验，利用先前合成的类似物与 将执行各种功能选择性概况，以识别D1R结构元素 对于𝜷-arr2偏见很重要。这些结果将提供关键的结构信息，以帮助推断结构 D1R募集的𝛽-ARR2的机制和结构功能性关系（SFSR） 将进一步的脚手架优化告知潜在的𝛽 rard2偏置化合物。 该项目的发现将通过提供化学工具来大大提高该领域的知识 将能够研究D1R处的偏置信号传导以及如何下游的分子途径 接收器有助于PD和盖子病理生理。从此类研究中获得的见解将提供 重要的线索指导新型的治疗方法，以解决这个具有挑战性的，未解决的医学问题。 呢