# Neurotensin receptor 1 as a novel target for opioid use disorder and discovery of new small molecule probes

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $716,226

## Abstract

PROJECT SUMMARY
Submitted in response to RFA-DA-24-063, we propose to develop novel, brain-penetrant, small molecule biased
allosteric modulators (BAMs) of the neurotensin receptor 1 (NTSR1) to attenuate relapse to opioid seeking in
individuals with opioid use disorder (OUD). NTSR1 is a G protein coupled receptor (GPCR) that is highly
expressed in dopamine (DA)-rich brain regions and modulates brain DA signaling. NTSR1 ligands counter the
effects of multiple classes of misused drugs. As a GPCR, NTSR1 signals via heterotrimeric G proteins and β-
arrestin proteins. While NTSR1 has long been recognized as a promising target for the treatment of chemical
addictions, development of balanced NTSR1 agonists that active both pathways is precluded by on-target side
effects (i.e., hypothermia, hypotension). Our collaborative team developed a series of first-in-class β-arrestin
BAMs of the NTSR1, which attenuate psychostimulant drug effects without the side effects characteristic of
balanced NTSR1 activation. While NTSR1 is a well-established therapeutic target for stimulant use disorders,
and its mechanism of action suggests utility that spans drug class, its validity as a target for OUD has not been
rigorously established. The limited data available on NTSR1’s effect on opioid action is promising. Our data
suggest that first generation β-arrestin NTSR1 BAMs act via a reward mechanism conserved across drug classes
and attenuate both stimulant and opioid drug self-administration. In aim 1, we will validate NTSR1 as a drug
target for the treatment of OUD with our optimized lead BAMWe will leverage a mouse model of relapse to
intravenous (IV) opioid seeking, NTSR1 knockout (NTSR1-/-) mice, and our extensive knowledge of β-arrestin
BAM pharmacology. Recently, we discovered that these compounds block NTSR1 signaling via some G
proteins, but permit signaling via others. Because balanced NTSR1 agonists promote drug seeking, we
hypothesize that this G protein permissiveness detracts from the therapeutic utility of these BAMs in OUD. In
aim 2, we will discover next generation β-arrestin BAMs for NTSR1 with improved β-arrestin selectivity
to test this hypothesis. We conducted comprehensive signaling characterization for a panel of ligands from our
lead series. In addition, we have robust cell-based assays (and appropriate counter-screens) to reliably monitor
NTSR1 activation of more than 14 transducers. Leveraging these assets, we will conduct a medicinal chemistry
campaign to increase the potency and β-arrestin selectivity of BAM scaffold, with a flow scheme consisting of
cell-based receptor signaling assays and early assessment of ADME, brain penetration, and central NTSR1
engagement. We have stringent criteria for second-generation leads. Compounds that match this profile will be
advanced to efficacy testing in a model of relapse to IV remifentanil seeking in wild-type and NTSR1-/- mice. This
multidisciplinary research plan capitalizes on the unique scientific an...

## Key facts

- **NIH application ID:** 11020050
- **Project number:** 1R01DA061773-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Steven H Olson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $716,226
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11020050

## Citation

> US National Institutes of Health, RePORTER application 11020050, Neurotensin receptor 1 as a novel target for opioid use disorder and discovery of new small molecule probes (1R01DA061773-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11020050. Licensed CC0.

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