Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants

项目总结/摘要 多巴胺D4受体（D4 R）在认知、注意力和决策中起着重要作用。人类 DRD 4基因具有高度多态性，不同的变异与各种神经精神疾病相关。在 特别地，VNTR变体（三种主要的变体被称为D4.2R、D4.4R和D4.7R）与VNTR基因的表达有差异。 ADHD和物质使用障碍患者，D4.7R与ADHD患病率增加可靠相关 物质使用障碍（Substance Use Disorders，SUDs）确定D4 R信号传导的精确生理作用以及 理解D4 R变异在促成疾病状态方面的后果一直受到以下因素的阻碍： 缺乏具有高亲和力、足够选择性、特征激动剂-拮抗剂反应 和/或合适的体内活性。目前还没有已知的化合物对D4 R变体具有差异活性。 因此，我们寻求开发具有变体特异性活性的新的、优化的D4 R配体，以扩大我们的研究范围。 对D4 R功能的理解和潜在治疗化合物的开发。D4.7R已更改 与多巴胺D2受体（D2 Rs）或α2A肾上腺素能受体（α 2AR）异聚化的能力， 与更常见的D4.4R相比。我们的研究小组发现，D4 R激动剂A-412997产生差异表达， 在D4.7R或D4.4R处与D2 R或α2AR异聚化的信号传导，以及在Gαi1与Gα o 1处的差异信号传导。我们 将利用我们现有的A-412997类似物库，并创建新的合理设计的类似物，以识别 新的药理学工具将有可能克服目前对药物的理解的局限性， D4 R VNTR多态性的功能意义。新的D4 R配体也具有用作药物的潜力。 药物治疗SUD。由于没有FDA批准的药物用于治疗 精神兴奋剂使用障碍，并且没有FDA批准的对D4 R有选择性的药物， 针对D4 R变体的工具可以满足多种需求。拟议的研究旨在设计，合成， 并利用计算机建模方法评估新的配体， D4 R蛋白质结构形成选择性D4.2R、D4.4R和D4.7R配体。

PROJECT SUMMARY/ABSTRACT The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision-making. The human DRD4 gene is highly polymorphic, with different variants associated with various neuropsychiatric disorders. In particular, VNTR variants (the three major ones are termed D4.2R, D4.4R, and D4.7R) are differentially associated with ADHD and substance use disorders, with the D4.7R reliably associated with increased prevalence of ADHD and substance use disorders (SUDs). Determining precise physiological roles of D4R signaling as well as understanding the consequences of D4R variants in contributing to disease states has been hampered by the lack of suitable compounds with high affinity, sufficient selectivity, characterized agonist-antagonist responses, and/or suitable in vivo activity. Currently there are no known compounds with differential activity at D4R variants. Therefore, we seek to develop new, optimized D4R ligands with variant-specific activity to expand our understanding of D4R function and in the development of potential therapeutic compounds. D4.7R has altered ability to heteromerize with dopamine D2 receptors (D2Rs) or α2A adrenergic receptors (α2ARs), when compared to the more common D4.4R. Our team has discovered that D4R agonist A-412997 produces differential signaling at D4.7R or D4.4R heteromerized with D2R or α2AR, and differential signaling at Gαi1 versus Gαo1. We will leverage our existing library of A-412997 analogs, and create new rationally designed analogs, to identify new pharmacological tools will have the potential to surmount current limitations on the understanding of the functional significance of D4R VNTR polymorphisms. Novel D4R ligands also hold the potential to be used as pharmacotherapeutics for SUD. Since there are no FDA-approved medications for the treatment of psychostimulant use disorders, and no FDA-approved medications selective for D4R, novel pharmacological tools targeting D4R variants can address multiple needs. The proposed research seeks to design, synthesize, and evaluate new ligands using computational modeling approaches that exploit underexplored regions within the D4R protein structure to develop selective D4.2R, D4.4R, and D4.7R ligands.