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

项目摘要：迷幻药表现出非凡的前途，是快速效果和持久的抗抑郁药，但很少 5-HT2A受体存在选择性激动剂，这是诱导迷幻作用的主要目标在人类中。关于产生抗抑郁药所需的受体轮廓，许多挥之不去的问题仍然存在影响与迷幻效应，以及是否可以解散这些效应以产生有效的非 5-HT2A激动剂的迷幻抗抑郁药。我们的初步数据表明，许多原型对于5-HT2A受体而言，迷幻药不是选择性的。因此，仅对迷幻药的研究不足要回答这些长期存在的问题，而应该得到基于探测的方法。这个项目试图开发新的化学探针来解决i）5-HT受体选择性和ii）途径选择性的问题或在5-HT2A受体处有偏置激动剂。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设计。在AIM 1中，我们将探索构型限制的N-苯唑类似物，以达到最佳的5-HT2A选择性和工程师用于驱动偏见激动的替代。 AIM 2，我们将利用一个合理设计的特权脚手架显示有望为5-HT2A/5-HT1B/1D选择性激动剂，以及用于驱动配体的替代的工程师偏见。最后，在AIM 3中，我们将使用5-HT1B/1D/1F选择性的Triptan支架来替换这些受体亚型的偏置激动剂的变化。总体而言，该项目旨在产生选择性的5-HT 受体有偏见且平衡的激动剂探针对，研究界将为研究界提供质疑迷幻与抗抑郁药的潜力。最终，该项目将开始新的治疗心理健康问题的策略，并引入了5-羟色胺药物发现的新时代。 1