# Allosteric Modulation of the Mu-Opioid Receptor

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $648,048

## Abstract

Opioid drugs are highly effective analgesics but suffer from serious on-target side-effects. Principle among
these are addition liability and respiratory depression that have led to the current opioid crisis. These effects
together with other actions, including constipation and nausea and vomiting, also reduce the effectiveness of
opioids in the pain clinic. Thus, there is a vital need to develop new analgesics or to improve the clinical
profile of existing medications. Morphine and related opioids exert their effects by acting at the orthosteric
site on the mu-opioid receptor (MOR), i.e. the site where the endogenous opioid peptides bind. Recent
advances in our knowledge of the structure of G-protein coupled receptors (GPCRs) have highlighted the
possibility that GPCR function may be controlled by compounds binding at a separate, allosteric, site on the
receptors. In this regard positive allosteric modulators (PAMs) that act at MOR (MOR-PAMs) have been
identified. Previous experiments show these compounds act to allosterically modulate the orthosteric site and
so increase the binding affinity, potency and/or maximal response of MOR agonists, including endogenous
opioid peptides, in a probe-dependent manner. Preliminary experiments demonstrate that MOR- PAMs are
effective antinociceptive agents in vivo in the mouse and act by enhancing endogenous enkephalin activity,
thus avoiding the need for opioid drugs such as morphine and oxycodone. This in vivo activity should preserve
the temporal and spatial characteristics of neuronal signaling and so avoid compensatory mechanisms
induced by chronic MOR activation. This application moves the field forward by using structural biology and
computational methods to identify the allosteric binding site on MOR, aided by the development of new
allosteric probes to allow us to more clearly define the mechanism of allosterism, and further exploration of
preliminary findings that allosteric modulators work as effective pain relieving agents in vivo. Detailed
understanding of the actions of allosteric modulators of MOR will provide new information on mechanisms
by which MOR function may be controlled and, together with the identification of high affinity probes, will pave
the way for future drug development efforts of MOR modulators as novel analgesics that safely harness the
analgesic efficacy of MOR without addiction and respiratory depression.
RELEVANCE (See instructions):

## Key facts

- **NIH application ID:** 10830963
- **Project number:** 5R37DA039997-10
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** John R. Traynor
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,048
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830963

## Citation

> US National Institutes of Health, RePORTER application 10830963, Allosteric Modulation of the Mu-Opioid Receptor (5R37DA039997-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830963. Licensed CC0.

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