# An optimized screening platform for identifying and quantifying biased agonists as drugs for the treatment of Opioid Use Disorder

> **NIH NIH R44** · MONTANA MOLECULAR, LLC · 2022 · $315,386

## Abstract

Millions of Americans today have an opioid use disorder (OUD). Millions more misuse
opioids, and the crisis continues to grow. The goal of this proposal is to speed the
discovery of non-addictive analgesics by providing drug discovery teams with simpler,
more robust, more quantitative, assays for agonist bias. Driven by the urgency of the
problem we are seeking Fast Track support to create new assay and analytic tools for
drug discovery in OUD research. Our goal is to optimize and test new assays for
agonist bias at particular receptors that couple to both the Gi and β-arrestin signaling
pathway, and create new tools to improve the analysis of structure/activity relationships.
There are good reasons to search for biased agonists to the receptors identified in the
NIDA “top ten” list of medication development priorities. Biased agonists could activate
beneficial signaling pathways while avoiding those that cause adverse effects. Finding
these biased agonists is difficult: current assays for detecting bias, while established
and validated, suffer from drawbacks that are limiting translatability to animal models
and clinical studies. These include entirely different sets of experimental conditions for
measuring the different signaling pathways being compared and different time courses
of the response being measured. The latter results in time-dependence of the bias
measurement which complicates predictions of in vivo efficacy and complicates SAR
tables by adding extra variables.
Our new assay will simultaneously measure the kinetics of Gi and β-arrestin signaling in
living cells. This project will involved creating new tools as well as re-purposing ones
we have already developed to study non-OUD drug targets. The assay will be optimized
for use on standard fluorescence plate readers, and a data analysis toolbox will be
developed to simplify quantification of agonist bias based on kinetic measurements.
Phase I will complete the initial validation studies on the NOP opioid receptor, with goal
of demonstrating assay reliability and sensitivity milestones. Phase II will optimize the
assay for D3 dopamine, CB1 cannabinoid and OPRM1 opioid receptors and develop
the analysis toolbox for deployment on standard plate readers and software packages
commonly used in drug discovery. In the second half of Phase II, assays with detailed
protocols will be ready distribute to researchers who are developing new drugs for OUD.

## Key facts

- **NIH application ID:** 10334560
- **Project number:** 5R44DA050357-03
- **Recipient organization:** MONTANA MOLECULAR, LLC
- **Principal Investigator:** THOMAS E HUGHES
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $315,386
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334560

## Citation

> US National Institutes of Health, RePORTER application 10334560, An optimized screening platform for identifying and quantifying biased agonists as drugs for the treatment of Opioid Use Disorder (5R44DA050357-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10334560. Licensed CC0.

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