# Supplement: Chemical and Molecular Tools for Modulating GPCR Function

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $199,971

## Abstract

PROJECT SUMMARY/ABSTRACT
Evidence from human imaging, postmortem analysis, and animal models suggests that atrophy of neurons in
the prefrontal cortex (PFC) plays a key role in the pathophysiology of both neuropsychiatric and
neurodegenerative diseases. Structural changes—including retraction of dendritic arbors, loss of dendritic
spines, and reductions in synapse density—lead to functional deficits that manifest as impaired cognition,
decreased motivation, anhedonia, high anxiety, and increased impulsivity. Thus, therapeutic strategies aiming
to restore PFC structure/function have broad therapeutic potential. Psychoplastogens—small molecules that
promote structural and functional neuroplasticity in the PFC—produce both rapid and long-lasting therapeutic
effects after a single administration. However, many psychoplastogens, including ketamine and serotonergic
psychedelics, induce hallucinations, which greatly limit their therapeutic potential and clinical scalability.
Fortunately, increasing evidence suggests that the hallucinogenic effects of ketamine and psychedelics may not
be necessary for their therapeutic properties, and our group recently introduced the first non-hallucinogenic
psychoplastogens. The advent of non-hallucinogenic psychoplastogens represents an exciting new direction for
the treatment of many brain disorders, but there is an urgent need to further optimize their efficacy and safety
profiles. Our primary goals are to, 1) establish robust synthetic strategies to psychoplastogenic natural products
and chemical scaffolds that are amenable to medicinal chemistry, 2) develop high-throughput cellular assays for
assessing psychoplastogen efficacy and safety, and 3) advance new in vivo assays uniquely suited to evaluate
the long-lasting effects of psychoplastogens. Taken together, these efforts will enable structure-activity
relationship (SAR) studies of key psychoplastogenic scaffolds, filling the gap in our knowledge about which
structural motifs are critical for both psychoplastogenic and hallucinogenic effects. Ultimately, the work described
here will enable the rational design of safer, non-hallucinogenic alternatives to psychedelics for treating a wide
variety of neuropsychiatric and neurodegenerative diseases.

## Key facts

- **NIH application ID:** 11093869
- **Project number:** 3R35GM148182-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** David E Olson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,971
- **Award type:** 3
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11093869

## Citation

> US National Institutes of Health, RePORTER application 11093869, Supplement: Chemical and Molecular Tools for Modulating GPCR Function (3R35GM148182-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11093869. Licensed CC0.

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