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

开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具

• 批准号: 10682794
• 负责人: Comfort Ahenkan Boateng
• 金额: $ 44.7万
• 依托单位: HIGH POINT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682794
• 关键词: Address; Adrenergic Receptor; Affinity; Agonist; Attention; Attention deficit hyperactivity disorder; Cognition; Computer Models; DRD4 gene; Decision Making; Development; Disease; Dopamine D2 Receptor; FDA approved; Genetic Polymorphism; Goals; Human; Libraries; Ligands; Minisatellite Repeats; Minor; Molecular; Pharmaceutical Preparations; Physiological; Play; Prevalence; Receptor Signaling; Research; Role; Signal Transduction; Substance Use Disorder; Therapeutic; Variant; Work; analog; antagonist; design; in vivo; neuropsychiatric disorder; novel; pharmacologic; protein structure; rational design; receptor; receptor function; response; stimulant use disorder; tool

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.

项目概要/摘要 多巴胺 D4 受体 (D4R) 在认知、注意力和决策中发挥着重要作用。 DRD4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。 特别是，VNTR 变体（三个主要变体称为 D4.2R、D4.4R 和 D4.7R）存在差异相关 与 ADHD 和物质使用障碍有关，D4.7R 与 ADHD 患病率增加可靠相关 确定 D4R 信号传导的精确生理作用。 了解 D4R 变异对疾病状态的影响一直受到以下因素的阻碍： 缺乏具有高亲和力、足够选择性、具有激动剂-拮抗剂反应特征的合适化合物， 和/或合适的体内活性目前尚无已知的对D4R变体具有不同活性的化合物。 因此，我们寻求开发具有变体特异性活性的新的、优化的 D4R 配体，以扩大我们的研究范围。 对 D4R 功能和潜在治疗化合物开发的理解已经改变。 与多巴胺 D2 受体 (D2Rs) 或 α2A 肾上腺素能受体 (α2ARs) 异聚化的能力，当 与更常见的 D4.4R 相比，我们的团队发现 D4R 激动剂 A-412997 产生差异。 D4.7R 或 D4.4R 上的信号与 D2R 或 α2AR 异聚，以及 Gαi1 与 Gαo1 上的差异信号。 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理解的限制 D4R VNTR 多态性的功能意义 新型 D4R 配体也具有用作的潜力。 SUD 的药物治疗，因为尚无 FDA 批准的药物用于治疗 SUD。 精神兴奋剂使用障碍，并且没有 FDA 批准的选择性 D4R 药物，新型药理学 针对 D4R 变体的工具可以满足多种需求。 并使用计算建模方法评估新的配体，这些方法利用内未开发的区域 D4R 蛋白质结构以开发选择性 D4.2R、D4.4R 和 D4.7R 配体。