# Characterization, optimization, and development of dual mGlu2/3 positive allosteric modulators for opioid use disorder

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $6,445,203

## Abstract

PROJECT SUMMARY
Opioid Use Disorder (OUD) is a significant problem worldwide and a surge in methamphetamine (MA) use has
emerged in chronic opioid users. Given recent increases in co-abuse, there is a dire need for novel treatment
strategies that prevent relapse to drug use in both OUD and MA Use Disorder (MUD). Long-term drug exposure
induces enhanced glutamate (Glu)-mediated synaptic plasticity, which underlies excessive physiological and
behavioral responses to drug-related cues. Opioid and MA exposure also activate microglia and astrocytes,
promoting release of pro-inflammatory cytokines. All these factors increase the risk of relapse to drug use.
Normalization of aberrant Glu activity caused by chronic drug use represents a novel therapeutic strategy to
prevent relapse in OUD/MUD. The activation of metabotropic Glu receptor subtypes 2 and 3 (mGlu2/3) using
agonists or positive allosteric modulators (PAMs) decreases psychostimulant self-administration (SA) as well as
cue-induced reinstatement (RI) in animals. Moreover, preclinical studies indicate that mGlu2/3 activation has
promise for treating stress- and anxiety-related disorders in humans and can systematically augment sleep.
However, the relative contribution of mGlu2 versus mGlu3 activation for treating OUD/MUD is not yet known.
Activation of presynaptic mGlu2 autoreceptors results in downstream inhibition of Glu release in the nucleus
accumbens, which in turn attenuates drug RI. In addition, activation of mGlu3, which is highly expressed in
astrocytes, leads to the release of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). The
specific localization and signal transduction of mGlu2 and mGlu3 receptors lead to our overarching hypothesis
that dual activation of both mGlu2 and mGlu3 will provide a clear advantage for the treatment for OUD and MUD
over mGlu2 activation alone. We have recently synthesized and characterized SBI-0799220, a PAM with equal
potency for mGlu2 and mGlu3 and SBI-0801315, a PAM with >50-fold selectivity for mGlu2 vs mGlu3. Preliminary
data indicate that SBI-0801315 attenuates Oxy cue-induced RI and SA, and that SBI-0799220 attenuates MA
SA. However, a direct comparison of mGlu2/3 with mGlu2 PAMs in models of OUD and MUD has not yet been
conducted. The goal of this application is to advance mGlu2/3 PAMs as a novel treatment for preventing relapse
to OUD, examine their potential for treating MUD, and simultaneously optimize mGlu2/3 PAMs. We will determine
the in vivo efficacy of mGlu2/3 and mGlu2-preferring PAMs to attenuate Oxy/MA SA and RI, Oxy/MA-induced
withdrawal, MA-induced neuroinflammation, and opioid-induced antinociception in rats. Simultaneously, we will
optimize the pharmacological and pharmaceutical properties of our mGlu2/3 PAM series including absorption,
distribution, metabolism, excretion, and pharmacokinetics. We have assembled a multidisciplinary team of
investigators that has the knowledge and experience to achieve these outc...

## Key facts

- **NIH application ID:** 10544440
- **Project number:** 1R01DA057120-01
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Nicholas David Cosford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $6,445,203
- **Award type:** 1
- **Project period:** 2022-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544440

## Citation

> US National Institutes of Health, RePORTER application 10544440, Characterization, optimization, and development of dual mGlu2/3 positive allosteric modulators for opioid use disorder (1R01DA057120-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10544440. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*