Supplement to Discovery of a high affinity, selective and beta-arrestinbiased 5-HT7R Agonist Grant

对高亲和力、选择性和 β 抑制偏向 5-HT7R 激动剂发现的补充补助金

• 批准号: 10799162
• 负责人: Seth Y Ablordeppey
• 金额: $ 9.91万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10799162
• 关键词: Addictive Behavior; Address; Adult; Affinity; Agonist; Alcohol abuse; American; Amino Acids; Attention; Automobile Driving; Behavioral; Behavioral inhibition; Biological Availability; Brain; Cardiovascular system; Central Nervous System Diseases; Characteristics; Chronic Insomnia; Cognition; Cognitive; Coupled; Desire for food; Development; Disease; Docking; Drowsy Driving; Drug Kinetics; Drug abuse; Electrons; Epilepsy; Evaluation; Family; Fragile X Syndrome; GTP-Binding Proteins; General Population; Goals; Grant; Homology Modeling; Hormonal Change; Hydrophobicity; Injury; Lead; Ligands; Memory; Metabolic; Migraine; Molecular Conformation; Moods; Motor; New Agents; Pain; Pain Threshold; Parents; Penetration; Pharmaceutical Preparations; Physiologic Thermoregulation; Play; Predisposition; Property; Psychophysiology; Public Health; REM Sleep; Reporting; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Architecture; Sleep Disorders; Sleeplessness; System; Testing; Tetrahydroisoquinolines; Therapeutic; Toxic effect; antagonist; autism spectrum disorder; beta-arrestin; design; effective therapy; falls; hydrophilicity; improved; in vivo; member; mouse model; non rapid eye movement; painful neuropathy; pharmacologic; pre-clinical; recruit; screening; serotonin 7 receptor; serotonin receptor; side effect; sleep pattern

Project Summary/Abstract: The 5-hydroxytryptamine 7 receptor (5-HT7R) is a member of the G protein- coupled 5-HT receptor family. Numerous studies have indicated that 5-HT7R plays a significant role in various behavioral and psychophysiological functions such as mood stability, cognitive and motor functions, behavioral inhibition, addictive behaviors, pain tolerance, sleep patterns, appetite, hormonal changes and thermoregulation. Pre-clinical findings have established the role of 5-HT7R in autism spectrum disorders, Fragile X syndrome (FXS), epilepsy, sleep disorders, neuropathic pain and migraine. Thus, 5-HT7R is emerging as a potential target for the treatment of various psychiatric and other associated disorders. Meanwhile, several 5-HT7R agonists, including AS-19, E-55888, LP-12, LP-44, LP-211, AGH-192 and compound 1g have been reported and their potential use in various CNS conditions (pain, memory and cognition), neuropathic pain, sleep disorders, alcohol and drug abuse are being investigated. However, the beneficial effects of activation or blockade of the 5-HT7R in each of these conditions is not often clearly established, primarily due to the lack of selective 5- HT7R agents. Even more critical is the absence of biased ligands that could clarify several controversial observations that relate to the 5-HT7R. Thus, our goal to design, synthesize and pharmacologically evaluate new agents with biased signaling towards G-Protein or β-arrestin signaling pathways hold great promise in understanding the 5-HT7R and its application to the treatment of various CNS disorders. There are three specific aims proposed in this application. Specific aim 1 will focus on extending our studies on the lead compounds (44080, 55933 and 57544) for their drug-like properties including brain penetration, pharmacokinetic studies, metabolic profiling, bioavailability assessments and cardiovascular toxicity predictions (HERG, 5-HT2BR). Based on the metabolic evaluations of lead compound 55933 from our preliminary studies, the synthesis and screening of new compounds is proposed in specific aim 2. This specific aim will also focus on the optimization and design of new agents to address the metabolic stability issues such as aromatization and glucuronidation observed in the preliminary studies. For this reason, aromatization susceptible tetrahydroisoquinoline (THI) moiety will be replaced with isoindoline which could not undergo aromatization and the CH2OH group will be replaced with substituents such as -F, -CONH2 to restrict glucuronidation while maintaining good drug-like characteristics. In addition, bioisosteric replacement of indanone with dihydronaphthalenone (DNO) moiety will be carried out. Furthermore, exploring the electron donating/withdrawing (σ values) and hydrophilic/hydrophobic (pi values) space around the THI/isoindoline ring systems with substituents such as Cl, OMe, CN, SOCH3 and NMe2, will reveal any improvements in their drug-like characteristics. Simultaneously, docking studies will be carried out using homology models to identify interactions with the key amino acid residues involved in inducing conformations associated with β-arrestin recruitment to the 5-HT7R. Specific Aim 3 will cover functional selectivity studies of lead 5-HT7R ligands for their agonist/antagonist properties and G-Protein or β-arrestin signaling bias followed by evaluation of their effect on sleep architecture and NREM/REM sleep pattern under in vivo conditions. Finally, selected test compounds will be compared with SB269970 (5-HT7R antagonist) and compound 1g, a 5-HT7R partial agonist (as a positive control) for their effect on NREM/REM sleep pattern and correlation of β-arrestin biased activity using a mice model. Project Summary/Abstract Page 6

项目摘要/摘要：5-羟色胺 7 受体 (5-HT7R) 是 G 蛋白的成员 大量研究表明5-HT7R在多种受体中发挥着重要作用。 行为和心理生理功能，例如情绪稳定性、认知和运动功能、行为 抑制、成瘾行为、疼痛耐受性、睡眠模式、食欲、荷尔蒙变化和体温调节。 临床前研究结果已确定 5-HT7R 在自闭症谱系障碍、脆性 X 综合征中的作用 (FXS)、癫痫、睡眠障碍、神经性疼痛和偏头痛因此，5-HT7R 正在成为一个潜在的靶点。 用于治疗各种精神疾病和其他相关疾病 同时，几种 5-HT7R 激动剂， 包括 AS-19、E-55888、LP-12、LP-44、LP-211、AGH-192 和化合物 1g 已被报道，其 潜在用于各种中枢神经系统疾病（疼痛、记忆和认知）、神经性疼痛、睡眠障碍、 然而，酒精和药物滥用的激活或阻断的有益效果正在研究中。 5-HT7R 在这些情况中的每一种情况通常都没有明确确定，主要是由于缺乏选择性 5- 更重要的是没有偏向配体，这可以澄清一些有争议的问题。 因此，我们的目标是设计、合成和药理学评估。 具有针对 G 蛋白或 β-arrestin 信号通路的偏向信号传导的新药物在 了解 5-HT7R 及其在治疗各种中枢神经系统疾病中的应用。 本申请提出了三个具体目标，具体目标 1 将侧重于扩展我们的目标。 对先导化合物（44080、55933 和 57544）的药物样特性（包括脑功能）的研究 渗透、药代动力学研究、代谢分析、生物利用度评估和心血管 毒性预测（HERG、5-HT2BR）基于我们对先导化合物 55933 的代谢评估。 初步研究，具体目标2中提出了新化合物的合成和筛选。该具体目标 Target还将重点关注新药物的优化和设计，以解决代谢稳定性问题，例如 正如在初步研究中观察到的芳香化和葡萄糖醛酸化，因此，芳香化。 易受影响的四氢异喹啉 (THI) 部分将被无法进行的异吲哚啉取代 芳构化，CH2OH基团被-F、-CONH2等取代基取代以限制 葡萄糖醛酸化同时保持良好的药物样特性，此外，生物电子等排替代。 将进行茚满酮与二氢萘酮（DNO）部分的反应。 THI/异吲哚啉周围的给予/撤回（σ值）和亲水/疏水（pi值）空间 具有 Cl、OMe、CN、SOCH3 和 NMe2 等取代基的环系统将揭示其性能的任何改进 同时，将利用同源模型进行对接研究以鉴定。 与参与诱导与 β-arrestin 相关的构象的关键氨基酸残基的相互作用 5-HT7R 的招募将涵盖先导 5-HT7R 配体的功能选择性研究。 它们的激动剂/拮抗剂特性和 G 蛋白或 β-抑制蛋白信号传导偏差，然后评估它们的 最后，在体内条件下对睡眠结构和 NREM/REM 睡眠模式的影响。 化合物将与 SB269970（5-HT7R 拮抗剂）和化合物 1g（5-HT7R 部分激动剂）进行比较 （作为阳性对照）对 NREM/REM 睡眠模式的影响以及 β-arrestin 偏向活动的相关性 使用鼠标模型。 项目总结/摘要第 6 页