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

Project Narrative: Psychedelics have shown promise for the treatment of depression and other mental health disorders. However, many questions remain on what mechanisms and pharmacological profiles psychedelics must possess for anti-depressant potential. This proposal seeks to develop chemical probes for key serotonin receptors known to be activated by psychedelics for the purpose of determining which signaling pathways and receptors are necessary for psychedelic versus therapeutic potential. 1