# Development of G protein beta gamma subunit inhibitors to improve the safety and efficacy of opioid analgesics

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $708,318

## Abstract

This application proposes a novel approach to improving the safety of opioid analgesics by post-receptor
pharmacological targeting of G protein  subunits to modify the actions of -opioid receptors (MORs). Our
laboratory has identified small molecule inhibitors of G protein  subunits that demonstrate in vivo efficacy in
various animal models of disease. Relevant to this application, we identified two related G inhibitors, M119
and gallein that increase MOR agonist analgesic potency in mice without potentiating side effects that include
development of tolerance, respiratory depression, constipation or addiction. Thus co-administration of G
inhibitors with opioid analgesics has the potential to improve their safety profile by opening up the therapeutic
window between analgesic efficacy and deleterious side effects. We propose that gallein and M119 modify opioid
action by blocking specific feedback pathways downstream of MORs while leaving pro-analgesic pathways
intact. MORs couple to the Gi family of G proteins and promote analgesia through G protein-dependent inhibition
of neurotransmitter release via G-dependent regulation of K+ (GIRK) channels, N-type Ca2+ channels and
inhibition of vesicle fusion with synaptic membranes. At the same time G activates feedback pathways
including phospholipase C (PLC) and G protein-coupled receptor kinases (GRKs), which limit opioid receptor
activity. Gallein and M119 block G-dependent regulation of PLC and GRK2 without blocking GIRK or N-type
Ca2+ channels and thereby biasing MORs toward pro-analgesic signaling. Gallein and M119 have been powerful
probe compounds to validate the idea that pharmacological G blockade could improve the properties of opioid
analgesics, but the chemical characteristics of the molecules makes them unsuitable for therapeutic
development. Data with new chemical series’ derived from our high throughput screening (HTS) campaign
support a G on-target mechanism of action. The primary goal of this application is to develop and
mechanistically characterize novel “drug like” G inhibitors that can be utilized to improve the safety of opioid
analgesics. This application is divided into 3 specific aims 1) We will diversify the chemistry of promising lead
compounds derived from HTS with the goal of improving potency and “drug like” characteristics. We expect that
upon completion of this aim we will identify a high potency “drug like” G inhibitor that can be a strong lead
candidate for therapeutic development. 2) We will use whole animal PLC and -arrestin-2 knockout models,
and brain slice electrophysiology to examine the roles of blocking feedback inhibition of MOR signaling by PLC,
PKC and -arrestin pathways in the potentiating actions of G inhibitors. 3) There is a significant need to find
an opioid analgesic for the treatment of chronic pain without abuse potential and adverse side effects. We will
explore the utility of G inhibition in chronic opioid use in a mou...

## Key facts

- **NIH application ID:** 10026089
- **Project number:** 5R01DA048625-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** EMILY M JUTKIEWICZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $708,318
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026089

## Citation

> US National Institutes of Health, RePORTER application 10026089, Development of G protein beta gamma subunit inhibitors to improve the safety and efficacy of opioid analgesics (5R01DA048625-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026089. Licensed CC0.

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