# Advancing mGlu1 positive allosteric modulators as therapeutics to facilitate abstinence in cocaine use disorder

> **NIH NIH R41** · ELEUTHERIA PHARMACEUTICALS LLC · 2022 · $325,386

## Abstract

Project Summary
A major challenge in treating cocaine use disorder is that vulnerability to cue-induced craving and relapse persist
even after long periods of abstinence. There is presently no FDA-approved medication to lessen cocaine craving.
The goal of Eleutheria Pharmaceuticals LLC is to develop metabotropic glutamate receptor 1 (mGlu1) positive
allosteric modulators (PAMs) as therapeutic agents to reduce craving and thereby facilitate abstinence in
persons with cocaine use disorder. The target, mGlu1, has been thoroughly validated by the lab of the PI and
Company Founder, and by other work. Our studies have used the ‘incubation of drug craving’ model, in which
cue-induced craving in rats progressively intensifies (‘incubates’) during abstinence and then remains high for
months. Incubation of craving also occurs in humans. We showed that incubation depends on strengthening of
glutamate synapses in a key brain region for drug craving (nucleus accumbens) via incorporation of atypical high
conductance AMPA-type glutamate receptors (CP-AMPARs). mGlu1 PAMs reverse this plasticity by eliciting a
form of long-term depression (LTD) that is expressed by CP-AMPAR internalization and, through this mGlu1-
LTD, reduce cocaine craving. In 2020, the PI obtained a NIDA U18 grant that has taken our project to the Assay
Development stage. In this Phase I STTR application, we propose two Aims that will result in the identification
of novel chemotypes and position us to apply for Phase II STTR funding. Classic in vitro screens for mGlu1
activation rely on detecting Ca2+ mobilization in cell lines. We have developed a novel assay to selectively detect
activation of the signaling pathway downstream of mGlu1 that mediates craving reduction, namely the rapid
translation of the LTD protein oligophrenin-1 (OPHN1). Briefly, HiBiT-tagged OPHN1 (stably transfected into an
mGlu1 over-expressing cell line) generates a luminescent signal upon mGlu1 stimulation. Aim 1 will optimize
this assay so it can be used in high throughput screening in Aim 2. The assay will be optimized by reduction of
baseline signal to achieve an optimal signal window and Z’ ≥ 0.6 as a benchmark for success. Reproducibility at
scale will be evaluated during a pilot screen of 1430 unique compounds tested in triplicate at a single dose. In
Aim 2, the optimized assay will be used for a quantitative high throughput primary screen of 4382 bioactive
compounds at Oregon State University’s High-Throughput Screening Services Laboratory. Hits from this screen
and additional compounds chosen for similarity to our mGlu1 PAM tool compound will be sourced fresh for dose
curves and cytotoxicity assessment, and medicinal chemistry prioritization conducted. If we are successful in
achieving our Phase I goals (optimize and execute the primary screen, identify and validate hit scaffolds), we
will submit a Phase II application to assess prioritized compounds in secondary assays, optimize their activity
and PK properties...

## Key facts

- **NIH application ID:** 10577196
- **Project number:** 1R41DA057437-01
- **Recipient organization:** ELEUTHERIA PHARMACEUTICALS LLC
- **Principal Investigator:** Marina Elizabeth Wolf
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $325,386
- **Award type:** 1
- **Project period:** 2022-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10577196

## Citation

> US National Institutes of Health, RePORTER application 10577196, Advancing mGlu1 positive allosteric modulators as therapeutics to facilitate abstinence in cocaine use disorder (1R41DA057437-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10577196. Licensed CC0.

---

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