Discovery of functionally selective dopamine ligands for age-related cognitive decline

项目总结/摘要 多巴胺D1样受体（D1 R）激动剂一直被证明可以增强认知能力， 功能（例如，工作记忆）。 D1 R还在突触可塑性和认知过程的调节中发挥重要作用 在与年龄相关的认知能力下降，如阿尔茨海默病（AD）。受体功能选择性/偏倚 信号传导是发现具有激活差异信号传导途径能力的药物的有用方法 由单一受体介导。我们最近的工作表明，D1功能选择性对 调节年轻成年大鼠前额叶皮层中与工作记忆相关的行为和神经生理学。 这些和其他数据表明，功能选择性D1配体可能是年龄相关的有希望的候选者。 认知能力下降在这里，我们提出了一个发现项目，以了解信号偏差如何影响认知 D1配体的作用，并针对可能成为潜在IND的新型功能选择性D1激动剂 用于年龄相关的认知衰退的药物治疗的候选者。这将由 遵循三个迭代但也是独立的具体目标，利用三个领域的最新进展，体外 药理学、体内行为和生理神经科学以及计算机模拟配体靶向机制研究。 目的1将检查D1的差异激活所表现的行为和神经生理学变化 老年大鼠与年轻大鼠（24个月老年大鼠和5个月年轻成年大鼠Fisher，TgF 344 转基因AD大鼠）。将通过工作记忆相关延迟改变测试预选的D1配体 反应任务中的T-迷宫，主要是因为它们对行为和神经生理学的影响。目标2将使用 用于配体-靶标模拟的计算方法，以开发机制并加速药物发现。目的 3将完成彻底的药理学筛选，以阐明年龄相关的最佳D1信号传导谱。 认知能力下降这将涉及受体结合特性的表征和功能测定，以及脱- 靶向分析，不仅在异源表达系统中，而且在脑组织中。圆满完成 提出的具体目标将提供有关功能选择性D1的潜在优势的启发性信息 与年龄相关的认知能力下降的激动剂。最近的临床研究表明，与早期的观点相反， D1 R是一个药物靶点。因此，本研究将为新的候选人的选择提供一个合理的基础 用于未来的IND使能研究和临床试验。

PROJECT SUMMARY/ABSTRACT Agonists for dopamine D1–like receptors (D1R) consistently have been shown to enhance cognitive functions (e.g., working memory) in normal, lesioned, and aged murine and primate species, including humans. The D1R also plays important roles in the regulation of synaptic plasticity and cognitive process that are damaged during age-related cognitive decline such as in Alzheimer’s disease (AD). Receptor functional selectivity/biased signaling is a useful approach for discovery of drugs with ability to activate differentially signaling pathways mediated by a single receptor. Our recent work suggested D1 functional selectivity has critical influence in modulation of working memory related behavior and neurophysiology in the prefrontal cortex of young adult rats. These and other data suggested functionally selective D1 ligands could be promising candidates for age-related cognitive decline. Here we propose a discovery project to understand how signaling bias affects the cognitive effects of D1 ligands, and to target novel functionally selective D1 agonists that may become potential IND candidates for the pharmacological treatment of age-related cognitive decline. This will be accomplished by the following three iterative but also independent specific aims, using recent advances in three field, in vitro pharmacology, in vivo behavioral and physiological neuroscience, and in silico ligand-target mechanistic studies. Aim 1 will examine behavioral and neurophysiological changes manifested by differential activation of D1 signaling pathways in aged versus young rats (24-month elderly and 5-month young adult Fisher, TgF344 transgenic AD rats). Pre-selected D1 ligands will be tested by a working memory related delayed alteration response task in the T-maze primarily, for their effects on behavior and neurophysiology. Aim 2 will use computational methods for ligand-target simulation to develop mechanism and accelerate drug discovery. Aim 3 will complete a thoroughly pharmacological screen to elucidate optimal D1 signaling profiles for age-related cognitive decline. This will involve characterization of receptor binding properties and functional assays, and off- target analysis, in not only heterologous expression systems but also brain tissue. The successful completion of proposed specific aims will provide heuristic information on the potential advantages of functionally selective D1 agonists for age-related cognitive decline. Recent clinical studies have shown, contrary to earlier views, that the D1R is a druggable target. Thus, this project will provide a rational foundation for selection of novel candidates for future IND-enabling studies and clinical trials.