# Structural studies of psychedelic activity at the serotonin receptor 5-HT1A

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $45,152

## Abstract

PROJECT SUMMARY
The rise of interest in psychedelic medicine calls for further exploration of the mechanisms underlying the
therapeutic nature of these drugs. Serotonin receptors are well-established regulators of behavioral and
cognitive effects. In particular, the serotonin receptor 5-HT1A is a primary target of antidepressant, anxiolytic,
and antipsychotic medications. 5-HT1A is also a high-affinity target of multiple psychedelic drugs, but its role in
the physiological effects of psychedelics has been overlooked as the serotonin receptor 5-HT2A is suggested
to be the primary mediator of hallucinogenic effects. However, select psychedelics have equivalent or greater
affinity for 5-HT1A over 5-HT2A. This project seeks to determine the unique molecular details of psychedelic
binding and activity at 5-HT1A with structural and functional studies. Structures of a 5-HT1A-G-protein complex
bound to psychedelic and therapeutic drugs will be solved via cryo-electron microscopy, revealing ligand and
transducer binding interactions at near-atomic resolution. This project will also address the lack of receptor-
level information on psychedelic activity with a series of in vitro functional studies. Distinct signaling pathways
have been associated with therapeutic or undesirable effects at other G-protein coupled receptors. As such,
the activity of existing psychedelics at 5-HT1A and 5-HT2A will be characterized across two major signaling
pathways—G-protein and b-arrestin. Additionally, the psychedelic 5-methoxy-dimethyltryptamine (5-MeO-
DMT) is reportedly selective for 5-HT1A over 5-HT2A. This scaffold will be exploited. A series of 5-MeO-DMT
derivatives will be synthesized and tested to identify the pharmacophores conferring selectivity for 5-HT1A over
5-HT2A. This experiment will generate selective compounds useful for delineating the role of 5-HT1A in vivo. In
a parallel set of experiments, 5-HT1A will be mutagenized to identify individual residues that play a key role in
5-HT1A activity and signaling. These experiments will confirm structural observations and identify important
residues outside of 5-HT1A’s ligand binding pocket. The complementary results of structural and functional
experiments will serve as an invaluable resource for future in vivo and drug-design efforts. In summary, the
proposed studies will reveal the structural and chemical determinants of psychedelic activity at 5-HT1A and
generate novel psychedelic compounds with defined activity, which can be used in future studies to delineate
the precise role of 5-HT1A in psychedelic physiology.

## Key facts

- **NIH application ID:** 10607119
- **Project number:** 1F31MH132317-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Audrey Louise Warren
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $45,152
- **Award type:** 1
- **Project period:** 2022-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10607119

## Citation

> US National Institutes of Health, RePORTER application 10607119, Structural studies of psychedelic activity at the serotonin receptor 5-HT1A (1F31MH132317-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10607119. Licensed CC0.

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