# Development of GPR3 probes as a novel target for nicotine cessation

> **NIH NIH U18** · RESEARCH TRIANGLE INSTITUTE · 2020 · $316,773

## Abstract

Project Summary
Tobacco addiction remains a leading cause of death and disease worldwide. Although many individuals
express a desire to quit, available therapeutics have proven to be only moderately efficacious, with cessation
success rates <25% after one year. In this proposal, we will explore the role of G protein-coupled receptor 3
(GPR3) in modulating nicotine reinforcement and aversion. GPR3 is a constitutively active orphan receptor that
activates Gαs leading to increased levels of cAMP within cells. GPR3 is highly expressed in the medial
habenula, suggesting it may be a critical modulator of the habenulo-interpeduncular pathway that regulates
nicotine aversion. Thus, GPR3 is a novel therapeutic target for nicotine cessation that should be investigated
both pharmacologically and mechanistically. However, in vivo studies of GPR3 are restricted due to the limited
availability of small molecule ligands for this receptor. The goal of this project is to develop and test probes of
GPR3 for in vivo studies related to nicotine abuse. We created a stable HEK hGPR3 cell line and developed
multiple in vitro functional assays to evaluate compound activity. We conducted a preliminary structure activity
relationship (SAR) study around a GPR3 agonist scaffold and identified a lead compound. During this project,
we will conduct a medicinal chemistry campaign to synthesize analogs of our lead scaffold. In addition, we
have developed a GPR3 homology model to aid in our SAR analysis. We will determine the potency, efficacy,
and selectivity of potential GPR3 agonist probes as well as an initial ADME/PK profile. We hypothesize that
optimized probes of GPR3 will decrease self-administration of nicotine by increasing aversive effects through
stimulation of the MHb-IPN pathway. We will test the in vivo efficacy of lead GPR3 probes in altering
intravenous nicotine self-administration at various nicotine doses. Upon completion of this grant, we expect to
have a potent, selective GPR3 agonist probe validated in both cell-based functional assays, and behavioral
models of nicotine abuse. Novel GPR3 agonist probes developed under this application will serve as tools to
investigate the signaling mechanisms and in vivo functions of GPR3 within the context of health and disease.

## Key facts

- **NIH application ID:** 10106485
- **Project number:** 1U18DA052416-01
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Elaine Arrington Gay
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,773
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106485

## Citation

> US National Institutes of Health, RePORTER application 10106485, Development of GPR3 probes as a novel target for nicotine cessation (1U18DA052416-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10106485. Licensed CC0.

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