Novel Chemical Probes for Study of 5-HT2R Balance and Function

用于研究 5-HT2R 平衡和功能的新型化学探针

• 批准号: 9280897
• 负责人: SCOTT R GILBERTSON
• 金额: $ 26.14万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280897
• 关键词: Achievement; Agonist; Behavior; Behavior Control; Binding; Biochemical; Biology; Chemicals; Cocaine; Cocaine Dependence; Cues; Data; Dimerization; Equilibrium; Exhibits; HTR2A gene; Heterodimerization; Impulsive Behavior; Impulsivity; In Vitro; Individual; Instruction; Label; Ligands; Location; Pathway interactions; Pharmacology; Property; Proteins; Reaction; Relapse; Role; Science; Serotonin; Serotonin Receptor 5-HT2A; Signal Transduction; Testing; Time; addiction; craving; design; dimer; in vivo; innovation; neural circuit; novel; novel strategies; receptor; restoration; therapeutic development; tool

The Translational Addiction Sciences Center (TASC) is focused on understanding the role of disrupted serotonin (5-HT) signaling through the 5-HT2A receptor (S-HTZAR) and 5-HT2cR in relapse precipitated by impulsive behavior and craving in the face of cocaine-associated cues (cue reactivity). The mechanisms and neural circuitry through which the 5-HT2AR:5-HT2CR balance controls these behaviors are being explored in Projects 1 and 2, and accumulating data indicate that strategies incorporating combined 5- HT2AR antagonist/5-HT2cR agonist properties will prove particularly effective to suppress impulsivity and cue reactivity and reduce relapse. We have recently demonstrated for the first time that a 5-HT2A+2CR heteromer is found in vitro and ex vivo. These intriguing data raise the wholly-original possibility that these two receptors may directly dimerize and exhibit biochemical properties that are demonstrably distinct from those of its individual components. To explore these hypotheses, new pharmacological tools are required to study the role of 5-HT2AR:5-HT2CR signaling and to elucidate the potential functional impact of 5-HT2R dimerization. Our primary objectives are to develop novel molecules which (1) possess dual activity as a 5-HT2AR antagonist and S-HTacR agonist, and (2) enable structural and functional analyses of 5-HT2R dimerization. Project 3 is taking the novel approach of designing and synthesizing a 5-HT2AR antagonist tethered to a 5-HT2cR agonist; there have been very few cases in which different receptor ligands have been tethered together in an attempt to stimulate one receptor while blocking the other. The molecules synthesized in this Project will be used to study the biology of these proteins and will have the ability to bind to specific dimeric receptors and alter their effector pathways selectively (Project 2, Core B). Biotinylated and fluorescently-labeled molecules will also be synthesized to visualize the location and formation of receptor dimers in vitro and ex vivo. In addition to synthesizing selective bivalent ligands at the bench, an in vivo synthetic approach, using reactions templated by receptor dimers, will be developed to probe receptor dimerization and provide novel, new bivalent ligands. Achievement of these Aims will provide us with novel and innovative pharmacological tools necessary to conduct detailed analyses of the impact of 5-HT2A+2CR heterodimerization on the balance of 5-HT2R function, and to test the overarching hypothesis that pharmacological restoration of 5-HT2AR:5-HT2CR balance will minimize deleterious behaviors that promote relapse in cocaine dependence. R E L E V A N C E (See instructions): The need for new tools and proof-of-principle for therapeutics development is vitally translational and we will direct these efforts toward the creation of targeted serotonergic molecules with fundamentally new mechanisms of action for treatment of cocaine addiction.

转化成瘾科学中心 (TASC) 致力于了解成瘾障碍的作用 5-羟色胺 (5-HT) 信号通过 5-HT2A 受体 (S-HTZAR) 和 5-HT2cR 促进复发 面对与可卡因相关的线索（线索反应性）时的冲动行为和渴望。机制 5-HT2AR:5-HT2CR 平衡通过神经回路控制这些行为 项目 1 和 2 中进行了探索，并且积累的数据表明，结合了 5- HT2AR 拮抗剂/5-HT2cR 激动剂特性将被证明特别有效地抑制冲动和 提示反应性并减少复发。我们最近首次证明了 5-HT2A+2CR 异聚体存在于体外和离体中。这些有趣的数据提出了一种完全原始的可能性： 两个受体可能直接二聚化并表现出明显不同于 其各个组件的那些。为了探索这些假设，需要新的药理学工具 研究 5-HT2AR:5-HT2CR 信号传导的作用并阐明 5-HT2R 的潜在功能影响 二聚化。我们的主要目标是开发新型分子，其 (1) 具有双重活性： 5-HT2AR 拮抗剂和 S-HTacR 激动剂，以及 (2) 能够对 5-HT2R 进行结构和功能分析 二聚化。项目3正在采用设计和合成5-HT2AR拮抗剂的新方法 与 5-HT2cR 激动剂相连；很少有不同受体配体具有不同受体配体的情况 被束缚在一起，试图刺激一种受体，同时阻断另一种受体。分子 该项目中合成的将用于研究这些蛋白质的生物学，并将有能力 与特定的二聚体受体结合并选择性地改变其效应途径（项目 2，核心 B）。 生物素化和荧光标记的分子也将被合成以可视化位置和 体外和离体受体二聚体的形成。除了合成选择性二​​价配体之外 bench 是一种体内合成方法，使用以受体二聚体为模板的反应，将被开发用于 探针受体二聚化并提供新颖的二价配体。这些目标的实现将 为我们提供了进行详细分析所需的新颖和创新的药理学工具 5-HT2A+2CR异二聚化对5-HT2R功能平衡的影响，并测试总体效果 假设药理学恢复 5-HT2AR:5-HT2CR 平衡将最大限度地减少有害作用 促进可卡因依赖复发的行为。 相关性（参见说明）： 治疗方法开发对新工具和原理验证的需求至关重要，我们将 将这些努力导向创建具有全新功能的靶向血清素分子 治疗可卡因成瘾的作用机制。