# Designing and developing PAM-antagonists for GPR68

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $202,775

## Abstract

PROJECT SUMMARY/ABSTRACT
GPR68 is an understudied orphan G-protein coupled receptor (GPCR). It can sense extracellular pH changes,
therefore functioning as a H+-sensing receptor. It couples to multiple signaling pathways and is implicated in
many biological processes, including pH homeostasis, inflammation, and vascular physiology. It is expressed
in most cells, but most abundantly in the brain, especially hippocampus – the brain region that is critical to
learning and memory and can also be affected in brain or mental disorders with cognitive deficits. Underlying
molecular mechanisms of GPR68 pharmacology and biology are not clear and yet to be defined.
Pharmacological studies with GPR68 have been hindered by the lack of small molecule tool compounds that
can be used to selectively activate or inhibit its activity. Selective tool compounds for GPR68 are urgently
needed. In 2015, we discovered the first small molecular ligand, ogerin, a positive allosteric modulator (PAM)
of GPR68, providing the first tool compound to selectively activate GPR68 (Huang et al., Nature 2015). This
selective probe led to the discovery that GPR68 suppresses contextual- but not cue-dependent learning and
memory in wild-type but not GPR68 knock-out mice, the first evidence indicating a role for GPR68 in cognition.
This observation suggests a potential link between GPR68 activation and cognitive deficits associated with
brain injuries and certain brain disorders, such as schizophrenia and neurodegenerative disease; these
conditions are usually associated with inflammation and brain regional acidosis (reduced pH), which could
activate GPR68. To study GPR68 pharmacology and to demonstrate if blocking GPR68 activation can help
learning and memory or reduce cognitive deficits, especially under weak acid conditions, selective GPR68
antagonists are needed. A current gap in our ability to exploit these possibilities is the lack of a small molecule
antagonist for GPR68, that can selectively block its activity in pharmacological assays. Our recent discovery
of the first selective GPR68 PAM-antagonist, MS27101, is a crucial step forward towards discovering such a
selective inhibitor, and is the focus of this application. Allosteric modulators such as ogerin bind to GPR68 at a
site different from that of H+, and fine tune H+ activity through increasing or reducing H+ affinity (-
cooperativity), efficacy (-cooperativity), or both. In contrast to traditional orthosteric agonists or antagonists
which rely on binding affinity for selectivity, allosteric modulators achieve high selectivity through allosteric 
cooperativity in addition to binding affinity (KB). PAM-antagonists are a unique type of negative allosteric
modulator (NAM) with affinity cooperativity >1 and efficacy cooperativity <1. Specifically, MS27101 affinity
(KB) is enhanced by H+ (because of >1), locking it into its binding pocket to block H+ activity (because of <1)
only under acidic conditions, while it remains...

## Key facts

- **NIH application ID:** 9967124
- **Project number:** 5R21MH120422-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Xi-Ping Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,775
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967124

## Citation

> US National Institutes of Health, RePORTER application 9967124, Designing and developing PAM-antagonists for GPR68 (5R21MH120422-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967124. Licensed CC0.

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