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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

项目总结: