# Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics

> **NIH NIH UH3** · VANDERBILT UNIVERSITY · 2022 · $76,619

## Abstract

Project Summary
An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators
(NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for
treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious
adverse effects and abuse liability associated with opioids. While a number of mGlu5 NAMs have been advanced
to clinical testing, the previous compounds all suffer from serious shortcomings, including poor pharmacokinetic
properties and toxicity that have prevented their further development. Therefore, these prior compounds have
not allowed for clinical studies to rigorously test this hypothesis in patients. We have developed a novel series
of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have excellent properties
for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5
NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in
migraine patients, we anticipate that our compounds will have broad-spectrum analgesic activity in patients with
a variety of chronic pain conditions. It will be essential that new pain drugs do not suffer from abuse liability or
severe toxicity that would prevent chronic administration, and these issues are addressed in the current research
plan. We have completed the lead optimization and in vivo pharmacokinetic (PK) studies and identify multiple
preclinical candidates. Preclinical proof of concept studies will now be conducted with our lead compound to test
the hypothesis that mGlu5 NAMs will be efficacious in the treatment of pain without abuse liability. Additionally,
we will perform positron emission tomography studies to determine in vivo receptor occupancy on the lead
candidate. Efficacy data from these studies will be used to clearly establish a PK/PD/CNS receptor occupancy
relationship and inform human dose projections and advance the program to the campaign 1 phase of the UH3
phase of this HEALS award. If UG3 milestones are met, a UH3 phase, in partnership with NIH contractors, will
include all chemistry, manufacturing and control (CMC) and possibly safety pharmacology and toxicology studies
required to prepare a preclinical candidate (PCC) for an investigation new drug (IND) application submission.

## Key facts

- **NIH application ID:** 10581793
- **Project number:** 3UH3NS116218-02S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** P Jeffrey Conn
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,619
- **Award type:** 3
- **Project period:** 2019-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10581793

## Citation

> US National Institutes of Health, RePORTER application 10581793, Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics (3UH3NS116218-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10581793. Licensed CC0.

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