# Chemical and Molecular Tools for Modulating GPCR Function

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $375,567

## 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:** 10551701
- **Project number:** 1R35GM148182-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** David E Olson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $375,567
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10551701

## Citation

> US National Institutes of Health, RePORTER application 10551701, Chemical and Molecular Tools for Modulating GPCR Function (1R35GM148182-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10551701. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*