# A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $876,038

## Abstract

PROJECT SUMMARY
Nowhere is the need for disease modifying therapeutic compounds more urgently needed than in the treatment
of mental health disorders. Despite significant advances in pharmaceutical and behavior interventions, mental
illnesses such as schizophrenia, depression and anxiety, combined with substance abuse disorders remain a
significant and growing burden to society. Orphan G-protein coupled receptors (oGPCRs) represent an
untapped reservoir of potential new drug targets for these diseases but the lack of pharmacological tools
needed to validate these targets prevents their therapeutic exploitation. As a first step towards tapping this
reservoir to develop new classes of medicines, we propose to find compounds that bind the oGPCRs and can
be used to validate them as drug targets. Leveraging recent high-resolution gene expression maps of
important brain circuits, we identified 27 oGPCRs whose discrete patterns of expression in the human brain
make them high value neuroscience drug targets. These were further prioritized based on the body of
biological data available for each receptor (e.g. genetics, linkage to disease) with the goal of focusing on
oGPCRs of greatest relevance to mental health. For the top 10 priority targets we will conduct high-throughput
screens against a library of ~50,000 compounds using an innovative ligand-induced forward trafficking assay
we recently published. In this assay, each oGPCR is engineered to be retained in the endoplasmic reticulum in
a state in which forward transport is enabled by the binding of a ligand. Trafficking of the oGPCR is then
monitored using a split beta-galactosidase reporter system. In this way, compounds (hits) that bind and induce
a conformational change in the oGPCR will be identified. Using a panel of cross and counter screen assays,
hits will be confirmed and shown to engage native oGPCR. Medicinal chemistry will be used to improve
potency and selectivity, and to generate chemical probes with physicochemical attributes suitable for use in
cellular assays exploring the function and pharmacology of target oGPCRs. Selectivity of probes will be
evaluated using a diverse panel of targets including GPCRs, ion channels, nuclear receptors and enzymes.
Where a specific oGPCR is highly expressed in human iPSC-derived neuronal cultures, we will investigate the
ability of probes to the specific receptor to affect neural networks using a microelectrode array assay system
we developed. We anticipate that these efforts will generate >10 novel probes against high priority oGPCRs.
Our intention is to rapidly distribute these to the scientific community to accelerate the understanding of these
brain enriched oGPCRs, contributing to their validation as drug targets for psychological disorders.

## Key facts

- **NIH application ID:** 10183333
- **Project number:** 5R01MH123826-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Michael Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $876,038
- **Award type:** 5
- **Project period:** 2020-06-05 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183333

## Citation

> US National Institutes of Health, RePORTER application 10183333, A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs (5R01MH123826-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10183333. Licensed CC0.

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