# Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $487,720

## Abstract

Summary/Abstract: GPR56/ADGRG1 is an Adhesion G protein Coupled Receptor (AGPCR) that is required
for brain development and function by acting as a critical regulator of the cellular pathway responsible for
myelin deposition in the brain. GPR56 mutations cause a debilitating human brain malformation disease. Our
recent work unveiled the general AGPCR activation mechanism. AGPCRs are two-fragment receptors that
arise from a single polypeptide following a defined self-cleavage event. The physical arrangement of the two
bound receptor fragments conceals a peptide sequence, that when revealed by fragment dissociation, serves
as a tethered-peptide self-activator (agonist) of the GPCR-like fragment. We used information from our
delineation of the AGPCR mechanism to engineer model GPR56 receptors in high and low activity states.
These receptors will be used to find small molecule compounds, through screening diverse chemical libraries,
that inhibit the high-activity receptors or activate the low-activity receptors. The immediate application of our
work will be to develop chemical probes that bind GPR56 for use in investigative studies of physiological
AGPCR activation mechanism(s). In the longer term, our chemical scaffolds may be developed as
therapeutics to correct defective brain myelination in a variety of disease contexts, including myelin-deficient
schizophrenia patients. GPR56 promotes nerve myelination by controlling the growth of oligodendrocyte
precursor cells (OPCs). OPCs become mature oligodendrocytes, which are the cells that wrap processes
around nerves in the brain to produce the protective myelin coat. Past studies in which OPCs were injected
into myelin-deficient rodent brains promoted nerve re-myelination and partial restoration of brain functions.
OPC injection into human brains would not be a tenable therapy at present, but use of a new GPR56 activating
drug to stimulate growth of natural OPCs might be a more realistic approach. The prospect of directing re-
myelination programs in damaged brains by artificially activating GPR56 is a highly appealing goal for patients
afflicted with diseases including schizophrenia or multiple sclerosis. We are confident that our endeavors to
develop probes for GPR56 will be successful, as our pilot screening efforts with small compound libraries
(5346 total compounds from four small libraries) identified a low-affinity, first-in-class GPR56 antagonist and a
partial agonist. It is the combination of our well-honed screen and counter-screen assays and our exquisitely
tuned G protein reconstitution secondary assays that made our pilot work successful. We are eager to apply
our established assays to the large chemical libraries and natural product extract collections at the University
of Michigan Center for Chemical Genomics to fulfill the critical, unmet need for AGPCR modulatory
compounds.

## Key facts

- **NIH application ID:** 9917826
- **Project number:** 5R01NS103946-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gregory Gordon Tall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $487,720
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917826

## Citation

> US National Institutes of Health, RePORTER application 9917826, Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism (5R01NS103946-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9917826. Licensed CC0.

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