# Assay development for characterization of Adrb3 antagonists as pain therapeutics

> **NIH NIH R03** · RESEARCH TRIANGLE INSTITUTE · 2021 · $196,439

## Abstract

PROJECT SUMMARY
Functional pain syndromes (FPS) affect over 100 million people, yet remain ineffectively treated by conventional
pharmacotherapies, such as opioids, that have poor efficacy and adverse central side effects. Our long-term
goal is to develop safer, more effective analgesics for patients with FPS, specifically peripherally-restricted
antagonists of the beta-3 adrenergic receptor (Adrb3). The Adrb3 receptor is a G protein-coupled receptor that
is activated by catecholamines. In clinical studies, we determined that patients with chronic FPS such as
fibromyalgia, low back pain, and irritable bowel syndrome have increased levels of catecholamines alongside
reduced levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines).
Consistent with clinical syndromes, we have shown that pharmacologic inhibition of COMT in rodents produces
pain at multiple body sites via activation of peripheral Adrb3. The pain is initiated by peripheral adipocyte Adrb3-
mediated increases in pro-inflammatory cytokines in local tissues and maintained by subsequent increases in
pro-inflammatory cytokines in spinal tissues and activation of mitogen activated protein kinases (MAPKs) in the
cell bodies and central terminals of pain-sensing nociceptors. Thus, Adrb3 is a novel and attractive target for the
treatment of chronic functional pain and pain-relevant inflammation. However, existing tool compounds either
lack selectivity for Adrb3 or have poor metabolic properties. To successfully build a robust drug discovery
platform for Abrb3 antagonists, in this proposal, we will develop and validate a battery of in vitro, cell-based
assays to fully characterize the pharmacology of novel Adrb3 ligands. The development of high throughput,
plate-based assays is critical for accurate evaluation of novel compound affinity, potency, efficacy, selectivity,
and target validation, as part of a long-term medicinal chemistry campaign that seeks to produce new analgesics
with improved specificity and side-effect profiles for the treatment of functional pain syndromes.

## Key facts

- **NIH application ID:** 10287083
- **Project number:** 1R03NS123731-01
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Elaine Arrington Gay
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,439
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287083

## Citation

> US National Institutes of Health, RePORTER application 10287083, Assay development for characterization of Adrb3 antagonists as pain therapeutics (1R03NS123731-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10287083. Licensed CC0.

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