# Development of MRGPRX1 positive allosteric modulators as non-addictive therapies for neuropathic pain

> **NIH NIH UH3** · JOHNS HOPKINS UNIVERSITY · 2021 · $1,524,982

## Abstract

Project Summary
Neuropathic pain remains a challenging condition to treat, as all currently available drugs fail to achieve
adequate pain relief in a significant proportion of patients. Although opioid-based analgesics have been
proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is
grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical
dependence, tolerance, and respiratory depression. Clearly, there is a critical unmet medical need for new
neuropathic pain therapies with improved efficacy and side effect profiles. Cumulative evidence suggests
that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited
side effects due to its restricted expression in nociceptors within the peripheral nervous system. BAM8-22, a
putative endogenous MRGPRX1 agonist, has shown analgesic efficacy in a variety of pain models following
intrathecal injection. While these findings open up the intriguing possibility for CNS-penetrant small molecule
MRGPRX1 agonists for the treatment of pain, direct activation of MRGPRX1 at peripheral terminals is
expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists.
Interestingly, submaximal levels of BAM22-derived peptides acting as endogenous MRGPRX1 orthosteric
agonists were detected at the spinal cord dorsal horn during persistent pain but remained undetectable in
the skin. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to
potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without
activating peripheral MRGPRX1. Indeed, intrathecal injection of a prototype MRGPRX1 PAM, ML382,
effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. Thus, the
central goal of this proposal is to develop a CNS-penetrant small molecule MRGPRX1 PAM that can be given
orally to treat neuropathic pain conditions. To accomplish the ultimate goal of assembling an IND application,
a team of independent investigators with complementary expertise has been assembled with many years of
research experience in the areas of medicinal chemistry, ADME, neuroscience, preclinical pain models, and
clinical pain management. Under this milestone-driven phased cooperative agreement, the team will work
closely with NIH program staff to accelerate the optimization and development of a promising MRGPRX1
PAM lead into a non-addictive therapeutic agent for the treatment of neuropathic pain conditions.

## Key facts

- **NIH application ID:** 10450294
- **Project number:** 4UH3NS115718-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Takashi Tsukamoto
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,524,982
- **Award type:** 4N
- **Project period:** 2019-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450294

## Citation

> US National Institutes of Health, RePORTER application 10450294, Development of MRGPRX1 positive allosteric modulators as non-addictive therapies for neuropathic pain (4UH3NS115718-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10450294. Licensed CC0.

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