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

项目摘要： 迷幻药作为快速起效和持久的抗抑郁药已经显示出非凡的前景，但很少有 存在5-HT 2A受体的选择性激动剂，5-HT 2A受体是诱导迷幻效应的主要靶点 在人类身上。许多挥之不去的问题仍然是产生抗肿瘤所需的受体概况。 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 迷幻抗抑郁药与5-HT 2A激动剂。我们的初步数据显示，许多原型 致幻剂对5-HT 2A受体没有选择性。因此，仅对致幻剂的研究是不够的 来回答这些长期存在的问题，而不是值得一个基于探测的方法。本项目谋求 开发新的化学探针，以解决i）5-HT受体选择性和ii）路径选择性的问题 或对5-HT 2A受体的偏向激动作用。我们的初步数据表明，上级5-HT 2A选择性 激动剂和5-HT 2A/5-HT 1B/1D混合激动剂可以使用基于结构的方法来设计。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-HT 2A选择性和工程 来驱动偏向性激动。目标2，我们将利用合理设计的特权支架， 显示出作为5-HT 2A/5-HT 1B/1D选择性激动剂前景，并在设计驱动配体的取代中进行工程改造 bias.最后，在目标3中，我们将使用5-HT 1B/1D/1F选择性曲坦支架来工程化取代， 这些受体亚型的偏向激动作用的变化。总体而言，本项目旨在产生选择性5-HT 受体偏向和平衡的激动剂探针对，这将提供给研究界的 迷幻药和抗抑郁药的区别最终，该项目将启动新的治疗方法， 精神健康问题的战略，并开创了一个新时代的血清素药物发现。 1

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