New 5HT2AR Target Identification and Assay Development for Discovering Psychoplastogenic Compounds

用于发现精神质体化合物的新 5HT2AR 靶标鉴定和检测开发

基本信息

批准号：
10742536
负责人：
Haifeng Eishingdrelo
金额：
$ 31.93万
依托单位：
BIOINVENU CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10742536
关键词：
Acceleration Affinity Aftercare Agonist Behavior Binding Biological Assay Brain Cell physiology Cerebral cortex Chromosome Pairing Clinical Complex Dangerousness Data Dendritic Spines Drug Addiction Drug Screening Drug Use Disorder Endocytosis Enzymes Experimental Designs G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins HTR2A gene Hallucinogens Health Professional Ketanserin Libraries Ligands Link Location Mediating Mental Depression Mental Health Mental disorders Molecular Mus Neurologic Neuronal Differentiation Neuronal Plasticity Neurons Opioid Receptor Pathway interactions Persons Phase Phosphotransferases Physiological Play Protein Isoforms Protein Kinase Proteins Receptor Signaling Research Rodent Role Scientist Screening Result Serotonin Antagonists Signal Pathway Signal Transduction Signaling Protein Technology Therapeutic Therapeutic Effect Therapeutic Equivalency Toxic effect antagonist assay development behavior test beta-arrestin drug action drug development drug discovery experience flexibility improved in vivo insight interest neurite growth neuroimaging neuropsychiatric disorder new therapeutic target novel therapeutics opioid use pharmacologic receptor receptor mediated endocytosis serotonin receptor side effect synaptogenesis therapeutic development trafficking transcription factor

项目摘要

Specific Aim: New 5HT2AR/14-3-3 isoform signal pathway identification and assay development for discovering psychoplastogenic compounds. Significance: Emerging data and limited clinical results show the promise of psychedelic drugs in the durable relief of people from seemingly untreatable psychiatric disorders and drug addictions. Neuroimaging evidence supports the concept that the brain after a psychedelic treatment becomes more flexible or `plastic', which is thought to be a component of its putative therapeutic effects. However, the side effects of psychedelics can be dangerous or even deadly. To develop new therapeutic options, we need to understand psychedelics underlying mechanisms of action. Many psychedelics act on the 5-HT2A serotonin receptor (5HT2AR), a G-protein Coupled Receptor (GPCR), to exert their effects. G-protein and β-arrestin signaling pathways cannot distinguish therapeutic and side effects of psychedelics. Importantly, the 5HT2AR antagonist ketanserin, can promote receptor endocytosis and still derive equivalent relief from depression-associated behaviors in mice, suggesting trafficking plays an important role. We studied GPCR/14-3-3 signal adaptor interactions using the LinkLight technology and found that GPCR/14-3-3 signals are closely related to receptor trafficking. Thus, studying 5HT2AR/14-3-3 signals mediated by psychedelics should shed light on understanding molecular mechanisms that contribute to psychedelic and therapeutic benefits, and develop new psychoplastogenic compounds. We have developed 5HT2AR/14-3-3ε and 5HT2AR/14-3-3γ LinkLight assays. We plan to develop additional 5HT2AR/14-3-3 isoform assays including 14-3-3β and 14-3-3ζ since a GPCR can differentially and temporally engage with 14-3-3 isoforms. Different 14-3-3 isoforms could display different functions. We plan to profile a panel of psychedelics in 5HT2AR/14-3-3 isoform assays and see if we can connect signaling pathways to physiological functions. In addition, we want to conduct a pilot screen to find compounds biased to the 14-3-3 signaling pathway without G-protein signals. Such biased compounds could lead us to better understand psychedelics' underlying mechanisms of action and develop new psychoplastogenic compounds. Experimental Design: Task 1. Develop additional 5HT2AR/14-3-3β and 5HT2AR/14-3-3ζ assays, profile 5HT2AR/14-3-3 isoform (ε, γ, β, & ζ) pathways with a panel of psychedelics including hallucinogenic and non- hallucinogenic agonists, as well as antagonists, and differentially and temporally characterize 5HT2AR/14-3-3 isoform signals. Task 2. Identify pathway-biased ligands by conducting a pilot screen with an in-house GPCR-focused library and characterize hits activities in 5HT2AR/14-3-3 isoforms, G-protein and β-arrestin pathway assays. Next Phase Plan: We expect to find multi-pathway biased ligands based on our results of screens using opioid receptor/14- 3-3 assays (unpublished results). These multi-pathway biased ligands will be evaluated for preliminary toxicity and DMPK activities and for in vivo rodent behavior tests and neuroimaging. The proof of concept studies will enable us to partner with potential collaborators to accelerate drug development.

具体目标：新的 5HT2AR/14-3-3 亚型信号通路鉴定和检测开发用于发现精神塑性化合物。意义：新出现的数据和有限的临床结果表明迷幻药物在持久缓解疼痛方面的前景患有看似无法治疗的精神疾病和毒瘾的人。支持这样的概念，即大脑在迷幻治疗后变得更加灵活或“可塑”，这被认为是其假定的治疗效果的一个组成部分，然而，迷幻药的副作用。可能是危险的，甚至是致命的，为了开发新的治疗方案，我们需要了解。致幻剂的潜在作用机制。许多迷幻药作用于 5-HT2A 血清素受体 (5HT2AR)，这是一种 G 蛋白偶联受体 (GPCR)，发挥其作用的G蛋白和β-arrestin信号通路不能区分治疗作用。重要的是，5HT2AR 拮抗剂酮色林可以促进受体。内吞作用，并且仍然能从小鼠抑郁相关行为中获得同等的缓解，这表明人口贩运发挥着重要作用。我们使用 LinkLight 技术研究了 GPCR/14-3-3 信号适配器相互作用，发现 GPCR/14-3-3信号与受体运输密切相关，因此，研究5HT2AR/14-3-3信号。由致幻剂介导的研究应该有助于理解有助于迷幻和治疗功效，并开发新的心塑性化合物。我们已经开发了 5HT2AR/14-3-3ε 和 5HT2AR/14-3-3γ LinkLight 检测。额外的 5HT2AR/14-3-3 同工型检测，包括 14-3-3β 和 14-3-3ζ，因为 GPCR 可以差异化并暂时与 14-3-3 同工型结合，不同的 14-3-3 同工型可以表现出不同的功能。我们计划在 5HT2AR/14-3-3 同工型测定中分析一组迷幻药，看看我们是否可以连接此外，我们希望进行试点筛选以找到生理功能的信号通路。偏向于 14-3-3 信号通路而无 G 蛋白信号的化合物。可以引导我们更好地理解致幻剂的潜在作用机制并开发新的精神塑性化合物。实验设计：任务 1. 开发额外的 5HT2AR/14-3-3β 和 5HT2AR/14-3-3ze 检测，分析 5HT2AR/14-3-3 同工型（ε、γ、β 和 ζ）通路与一组致幻剂，包括致幻剂和非致幻剂致幻剂激动剂以及拮抗剂，并进行差异和时间表征 5HT2AR/14-3-3 同工型信号。任务 2. 通过使用内部 GPCR 进行试点筛选来识别通路偏向配体文库并表征 5HT2AR/14-3-3 亚型、G 蛋白和 β-arrestin 通路的活性化验。下一阶段计划：我们期望根据我们使用阿片受体/14-的筛选结果找到多途径偏向配体 3-3 测定（未发表的结果）将对这些多途径偏向配体进行初步评估。毒性和 DMPK 活性以及体内啮齿动物行为测试和神经影像学的概念验证。研究将使我们能够与潜在的合作者合作，加速药物开发。