Discovery of a High Affinity, Selective and β-arrestin Biased 5-HT7R Agonist

发现高亲和力、选择性和β-抑制蛋白偏向的 5-HT7R 激动剂

• 批准号: 10412227
• 负责人: Seth Y Ablordeppey
• 金额: $ 14.8万
• 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/10412227
• 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; Circadian Rhythms; Cognition; Cognitive; Coupled; Desire for food; Development; Disease; Docking; Drowsy Driving; Drug Kinetics; Drug abuse; Electroencephalography; Electrons; Epilepsy; Evaluation; Family; Fragile X Syndrome; Functional disorder; GTP-Binding Proteins; General Population; Glucuronides; Goals; Homology Modeling; Hormonal Change; Human; Hydrophobicity; Hypothalamic structure; Injury; Isoenzymes; Lead; Learning; Ligands; Liver Microsomes; Locomotion; Memory; Mental Depression; Metabolic; Migraine; Molecular Conformation; Moods; Motor; New Agents; Pain; Pain Threshold; Pathology; Penetration; Permeability; Pharmaceutical Preparations; Pharmacology; Physiologic Thermoregulation; Play; Population; Property; Psychophysiology; Public Health; REM Sleep; Recovery; Reporting; Role; Sequence Homology; Signal Pathway; Signal Transduction; Sleep; Sleep Architecture; Sleep Disorders; Sleeplessness; System; Testing; Tetrahydroisoquinolines; Thalamic structure; Therapeutic; Toxic effect; X-Ray Crystallography; antagonist; autism spectrum disorder; base; beta-arrestin; design; drug discovery; effective therapy; falls; hydrophilicity; improved; in vivo; in vivo evaluation; member; mouse model; non rapid eye movement; painful neuropathy; pre-clinical; receptor; 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.

项目摘要/摘要：5-羟化性胺7受体（5-HT7R）是G蛋白的成员 耦合5-HT接收器家庭。许多研究表明，5-HT7R在各种 行为和心理生理功能，例如情绪稳定，认知和运动功能，行为 抑制作用，添加剂行为，疼痛耐受性，睡眠方式，食欲，激素变化和温度调节。 临床前的发现已经确定了5-HT7R在自闭症谱系中的作用，脆弱的X综合征 （FXS），癫痫，睡眠障碍，神经性疼痛和偏头痛。那是5-HT7R作为潜在目标的出现 治疗各种精神病和其他相关疾病。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，它们 在各种中枢神经系统条件（疼痛，记忆和认知），神经性疼痛，睡眠障碍中的潜在用途， 正在调查酒精和吸毒。但是，激活或阻塞的有益影响 在每种情况下，5-HT7R通常并未经常清楚地确定，这主要是由于缺乏选择性5-- HT7R代理。更重要的是缺乏有偏见的配体，这些配体可能会澄清一些有争议的 与5-HT7R有关的观察结果。这是我们设计，合成评估的目标 对G蛋白或β-arrestin信号通路有偏见信号传导的新代理在 了解5-HT7R及其在治疗各种CNS疾病的治疗中的应用。 本应用程序中提出了三个具体目标。具体目标1将专注于扩展我们的 研究铅化合物（44080、55933和57544）的研究，包括脑（包括脑） 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）。基于我们的铅化合物55933的代谢评估 在特定目标2中提出了初步研究，新化合物的合成和筛选。 AIM还将重点介绍新代理的优化和设计，以解决代谢稳定性问题 在初步研究中观察到的芳香化和谷化。因此，芳香化 易感四氢异喹啉（thi）部分将被等丁氨酸取代 Aromatization和CH2OH组将被诸如-f，-conh2之类的子接头代替以限制 葡萄糖醛酸化同时保持良好的药物样特征。另外，生物酶替代 将使用二氢甲乙烯酮（DNO）部分进行印酮。此外，探索电子 捐赠/提取（σ值）和亲水/疏水（PI值）空间周围/iSoindoline周围 带有子接头的环系统，例如CL，OME，CN，SOCH3和NME2，将揭示其其任何改进 类似药物的特征。同时，将使用同源模型进行对接研究以识别 与与β-arrestin相关的诱导构象所涉及的关键氨基酸的相互作用 招募5-HT7R。特定目标3将涵盖铅5-HT7R配体的功能选择性研究 他们的激动剂/拮抗剂特性以及G蛋白或β-arrest素信号传导偏见，然后评估其 在体内条件下对睡眠结构和NREM/REM睡眠模式的影响。最后，选定的测试 将化合物与SB269970（5-HT7R拮抗剂）和化合物1G进行比较 （作为阳性对照）它们对NREM/REM睡眠模式的影响以及β-arrestin偏置活性的相关性 使用小鼠模型。