Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential

基于结构的选择性血清素偏向激动剂设计作为迷幻潜力的化学探针

基本信息

批准号：
10712002
负责人：
John D McCorvy
金额：
$ 53.1万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2023-07-12 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10712002
关键词：
Address Agonist Antidepressive Agents Arrestins Chemicals Clinical Research Communities Data Development Disease Dissociation Drug Design Engineering Exhibits G-Protein-Coupled Receptors GTP-Binding Proteins Goals HTR2A gene Hallucinogens Head Human Investigation Lead Ligands Measures Mental Depression Mental Health Mental disorders Migraine Modeling Modification Molecular Conformation Nervous System Pathway interactions Pharmaceutical Preparations Phenethylamines Positioning Attribute Process Psilocybin Publishing Recruitment Activity Research Rodent Series Serotonin Serotonin Agents Serotonin Receptor 5-HT2A Signal Pathway Signal Transduction Structure Structure-Activity Relationship Technology Therapeutic Therapeutic Effect analog antidepressant effect beta-arrestin design diphenyl drug discovery in vivo novel pharmacologic piperidine preference prevent psilocin rational design receptor scaffold screening serotonin receptor treatment strategy triptans

项目摘要

Project Summary: Psychedelics have shown extraordinary promise as fast-acting and long-lasting anti-depressants, but few selective agonists exist for the 5-HT2A receptor, which is the principal target for induction of psychedelic effects in humans. Many lingering questions remain as to the receptor profile needed to produce anti-depressant effects versus psychedelic effects, and whether these effects can be dissociated to yield effective non- psychedelic anti-depressants with 5-HT2A agonism. Our preliminary data reveals that many of the prototypical psychedelics are not selective for the 5-HT2A receptor. Therefore, the study of psychedelics alone is insufficient to answer these long-standing questions and instead deserve a probe-based approach. This project seeks to develop novel chemical probes to address the problems of i) 5-HT receptor selectivity and ii) pathway-selective or biased agonism at the 5-HT2A receptor. Our preliminary data suggests that superior 5-HT2A-selective agonists, and 5-HT2A/5-HT1B/1D mixed agonists can be designed using a structure-based approach. In Aim 1, we will explore conformationally-restricted N-benzyl analogs to achieve optimal 5-HT2A selectivity and engineer in substitutions to drive biased agonism. Aim 2, we will utilize a rationally-designed privileged scaffold that shows promise as a 5-HT2A/5-HT1B/1D selective agonist, and engineer in substitutions designed to drive ligand bias. Finally, in Aim 3, we will use the 5-HT1B/1D/1F-selective triptan scaffold to engineer in substitutions to cause shifts in biased agonism at these receptor subtypes. Overall, this project aims to generate selective 5-HT receptor biased and balanced agonist probe pairs, which will available to the research community for the interrogation of psychedelic versus anti-depressant potential. Ultimately, this project will initiate novel treatment strategies for mental health issues and usher in a new era of serotonin drug discovery. 1

项目概要：迷幻药作为速效、长效的抗抑郁药已显示出非凡的前景，但很少有 5-HT2A 受体存在选择性激动剂，这是诱导迷幻效果的主要目标在人类中。关于生产抗抑郁药所需的受体概况，仍然存在许多挥之不去的问题效果与迷幻效果，以及这些效果是否可以分离以产生有效的非具有 5-HT2A 激动作用的迷幻抗抑郁药。我们的初步数据表明，许多原型致幻剂对 5-HT2A 受体没有选择性。因此，仅对致幻剂进行研究是不够的要回答这些长期存在的问题，应该采用基于探索的方法。该项目旨在开发新型化学探针来解决 i) 5-HT 受体选择性和 ii) 途径选择性问题或对 5-HT2A 受体的偏向激动作用。我们的初步数据表明，卓越的 5-HT2A 选择性激动剂和 5-HT2A/5-HT1B/1D 混合激动剂可以使用基于结构的方法进行设计。在目标 1 中，我们将探索构象限制的 N-苄基类似物，以实现最佳的 5-HT2A 选择性并设计替换以驱动有偏见的激动。目标2，我们将利用一个合理设计的特权脚手架显示出作为 5-HT2A/5-HT1B/1D 选择性激动剂的前景，并设计用于驱动配体的取代偏见。最后，在目标 3 中，我们将使用 5-HT1B/1D/1F 选择性曲坦支架进行替代设计，以引起这些受体亚型的偏向激动作用发生变化。总体而言，该项目旨在产生选择性 5-HT 受体偏向和平衡激动剂探针对，将提供给研究界询问迷幻药与抗抑郁药的潜力。最终，该项目将启动新的治疗方法心理健康问题的策略并开创血清素药物发现的新时代。 1