# Negative allosteric modulators for the management of Opioid Use Disorder

> **NIH NIH U18** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $234,000

## Abstract

Abstract
There is a significant need for new treatments for opioid use disorder (OUD) to manage patients abusing
heroin, fentanyl, oxycodone and related drugs. Buprenorphine and methadone are both effective medications
for OUD, but are agonists with potential for abuse and risk of respiratory depression. Moreover, they are not
effective in relapse situations. The antagonist naloxone is an alternative that does prevent relapse, but has
very poor patient compliance due to its complete blockade of the mu-opioid system. We have discovered
compounds that act as antagonists of the mu-opioid receptor (MOR), by a non-competitive mechanism. Such
compounds are allosteric antagonists also called NAMs or Negative allosteric modulators and reduce the
activity of MOR agonists in a fashion that is non-surmountable and that does not completely shut down the
receptor, thereby providing the ability to reduce opioid actions in dependent individuals, potentially without
negative side-effects of competitive antagonists like naloxone. Our long term goal is to identify NAMs as an
alternative, non-agonist treatment for OUD. Based on our previous work with positive modulators it is likely that
NAMs will also: a) show “probe dependence”, such that it could be possible to block opioid drugs without
affecting the activity of the endogenous opioid peptides and b) show bias, by blocking certain pathways
downstream of MOR associated with the rewarding and respiratory depressant-like actions without preventing
analgesia. Our long term hypothesis is that NAMS of MOR could be developed as effective non-agonist
treatments for OUD by directly targeting the site of action of abused opioids in a novel way. The objective of
the current application is to develop our original lead molecule to obtain a NAM for MOR that has high affinity
and IP potential. We will 1) Identify novel, improved NAMs by chemistry with HTS and 2) Determine the
mechanism of NAM action and demonstrate probe dependence and bias as well as perform preliminary proof
of concept studies in vivo. Completion of this project will initiate preclinical studies on the potential of NAMs for
the management of OUD.

## Key facts

- **NIH application ID:** 10105035
- **Project number:** 1U18DA052371-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Andrew Alt
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105035

## Citation

> US National Institutes of Health, RePORTER application 10105035, Negative allosteric modulators for the management of Opioid Use Disorder (1U18DA052371-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10105035. Licensed CC0.

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