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

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $516,972

## Abstract

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.
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## Key facts

- **NIH application ID:** 10886771
- **Project number:** 5R01MH133849-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** John D McCorvy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,972
- **Award type:** 5
- **Project period:** 2023-07-12 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886771

## Citation

> US National Institutes of Health, RePORTER application 10886771, Structure-based Design of Selective Serotonin Biased Agonists as Chemical Probes for Psychedelic Potential (5R01MH133849-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10886771. Licensed CC0.

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