Small-molecule probes for augmenting D5 receptor signaling

项目摘要 认知障碍是许多神经精神障碍的核心特征，与 患者的功能结局。目前的治疗选择是不够的，需要新的 治疗策略。多巴胺D1样受体家族(D1型和D5型受体)被认为是一种 改善认知功能的潜在目标。使用d1/d5全激动剂的临床研究显示前景看好 但这些化合物存在与不良反应特征相关的重大缺陷。缺乏 选择性配体以及d1和d5受体之间相当大的空间重叠使它 难以确定哪一种受体对该药物的特定疗效和不良反应特征负责 非选择性激动剂。人们一直在努力开发针对D1受体的选择性工具，但对于我们的 据了解，目前还没有正式的努力来确定D5选择性化合物。来自我们的最新研究 小组和其他人的研究表明，D5受体在认知功能中发挥着关键作用，特别是在 在神经精神障碍中，认知领域受到严重干扰。此外，多个D5选择性 与神经功能相关的信号通路已经被确定。不幸的是，进一步的实验 由于缺乏选择性配体，D5受体在神经生物学中的作用一直受到阻碍。在这 应用方面，我们建议设计和合成D5选择性的化学探针。由于高度的 D5和D1的同源正构结合位点，我们将重点介绍变构调节剂。一次 D5受体对D1受体的选择性已通过cAMP诱导试验建立，效价 将确定D5特异性信号级联的基于细胞的分析。化合物被证明是有效的和 然后，选择性的将接受代谢稳定性的体外筛选和针对广泛小组的反筛选 受体和离子通道。被发现代谢稳定且偏离目标最小的化合物 结合，将在体内进行测试，以确定他们是否有足够的血浆和脑暴露来接触D5 受体及药效学研究进展。最后，将对化合物进行测试以确定它们的能力 诱导脑源性神经营养因子在前额叶皮质的表达，这是一种通过D5受体传递信号的已知效应。一次 经过优化和表征，这些D5选择性探针将使我们能够进一步表征D5的作用 受体在神经功能中的作用，并确定它是否是一个可行的治疗靶点。

Project Summary Cognitive impairment is a core feature of many neuropsychiatric disorders that directly correlates with functional outcome for patients. Current treatment options are inadequate and there is a need for novel therapeutic strategies. The dopamine D1-like receptor family (D1 and D5 receptors) has been proposed as a potential target for improving cognitive function. Clinical studies with D1/D5 full agonists have shown promising efficacy, but these compounds suffer from significant drawbacks related to adverse effect profiles. The lack of selective ligands as well as considerable spatial overlap between the D1 and D5 receptors have made it difficult to determine which receptor is responsible for specific efficacy and adverse effect features of the nonselective agonists. There have been efforts to develop selective tools for D1 receptors but, to our knowledge, there have been no formal efforts to identify D5-selective compounds. Recent research from our group and others has shown that the D5 receptor plays a critical role in cognitive function, particularly in cognitive domains significantly disrupted in neuropsychiatric disorders. Additionally, multiple D5-selective signaling pathways relevant for neural function have been identified. Unfortunately, further experimentation to determine the role of the D5 receptor in neurobiology has been hindered by the lack of selective ligands. In this application, we propose to design and synthesize D5-selective chemical probes. Due to the high degree of homology between the D5 and D1 orthosteric binding sites, we will focus on allosteric modulators. Once selectivity for D5 receptors over D1 receptors has been established using cAMP induction assays, potency on cell-based assays of D5-specific signaling cascades will be determined. Compounds shown to be potent and selective will then undergo in vitro screening for metabolic stability and counterscreening against a broad panel of receptors and ion channels. Compounds that are found to be metabolically stable with minimal off-target binding, will be tested in vivo to determine if they have sufficient plasma and brain exposure to engage the D5 receptor and advance to pharmacodynamic assays. Finally, compounds will be tested to determine their ability to induce BDNF expression in the prefrontal cortex, a known effect of signaling through the D5 receptor. Once optimized and characterized, these D5-selective probes will allow us to further characterize the role of the D5 receptor in neural function and determine if it is a viable therapeutic target.