# Optimization of MrgX1 allosteric agonists as potential therapies for chronic pain

> **NIH NIH R33** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $392,500

## Abstract

Chronic pain is a major health and economic problem worldwide. Because the major analgesics (e.g., opioids)
bind to receptors that are widely expressed throughout the central nervous system (CNS), dose-limiting
adverse effects and significant risk of addiction and abuse present substantial barriers to their clinical use. Pain
sensing neurons (a.k.a nociceptors) in dorsal root ganglion (DRG) play essential role in pain transmission by
detecting painful signals in the periphery such as skin and viscera. Therefore, targeting molecules specifically
expressed in nociceptors may offer an opportunity for pain-selective pharmacologic interventions. Our previous
data have shown that Mrgs including mouse MrgC11 and human MrgX1 are specifically expressed in
nociceptors in DRG and constitute an endogenous anti-pain pathway. Funded R03 grant allowed us to identify
selective and potent MrgX1 allosteric agonists. Preliminary data showed that two allosteric agonists inhibited
persistent pain in humanized MrgX1 mice. MrgX1 allosteric agonists may potentially become novel anti-chronic
pain drugs with limited CNS-related side effects. In this proposal, we will improve and optimize MrgX1 allosteric
agonists and test their analgesic efficacy in mice. Highly selective agonists, and for the purpose of this
proposal, allosteric agonists, are needed in order to better understand the respective role of MrgX1 in these
studies of chronic pain. We have recently discovered a novel class of allosteric agonists with potency on
MrgX1 and selectivity against MrgX2. These selective allosteric agonists offer a unique opportunity to test the
hypothesis presented in this proposal. In order to develop first-in-class, potent, selective and CNS penetrant
MrgX1 allosteric agonists, we will optimize our lead scaffold such that the tool compound will possess the
appropriate properties, a balance of potency, selectivity and DMPK. We will utilize an iterative medicinal
chemistry approach which will enable all of the attributes to be evaluated in parallel. Once the tool
compound(s) have been determined, we will then test these compounds in the humanized MrgX1 mouse
model.

## Key facts

- **NIH application ID:** 10112868
- **Project number:** 5R33DA045303-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Corey R. Hopkins
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112868

## Citation

> US National Institutes of Health, RePORTER application 10112868, Optimization of MrgX1 allosteric agonists as potential therapies for chronic pain (5R33DA045303-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112868. Licensed CC0.

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