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

项目总结： 迷幻剂已经显示出作为快速有效和长效抗抑郁剂的非凡前景，但很少有 5-HT2a受体存在选择性激动剂，它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关于产生抗抑郁剂所需的受体 效果与迷幻效果，以及这些效果是否可以被分离以产生有效的非 迷幻抗抑郁药，5-HT2A激动剂。我们的初步数据显示，许多原型 迷幻剂对5-HT2A受体没有选择性。因此，仅对迷幻剂的研究是不够的。 来回答这些长期存在的问题，而不是应该采用基于探测的方法。这一项目旨在 开发新的化学探针以解决i)5-羟色胺受体选择性和ii)途径选择性问题 或5-HT2a受体的偏向激动症。我们的初步数据表明，优越的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， 我们将探索构象受限的N-苄基类似物，以实现最佳的5-HT2A选择性和工程化 以替代来驱动有偏见的激励性。目标2，我们将利用设计合理的特权脚手架 展示了作为5-HT2A/5-HT1B/1D选择性激动剂的前景，并设计了旨在驱动配体的替代 偏见。最后，在目标3中，我们将使用5-HT1B/1D/1F-选择性Triptan支架进行工程替换，以使 这些受体亚型的偏向激动感的转变。总体而言，该项目旨在产生选择性的5-羟色胺 受体偏向和平衡的激动剂探针对，将提供给研究界用于 询问迷幻药与抗抑郁药之间的关系。最终，该项目将启动新的治疗方法 针对精神健康问题的战略，并开启了5-羟色胺药物发现的新时代。 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