# Domain-specific inhibition of angiotensin-converting enzyme as a therapeutic strategy for opioid use disorders

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $1,771,799

## Abstract

ABSTRACT
This project combines the mutual expertise of Drs. Patrick Rothwell and Swati More (Principal Investigators) in
nucleus accumbens opioid signaling and medicinal chemistry. As part of an ongoing collaboration supported by
NIDA (R21 DA050120), we have found that angiotensin-converting enzyme (ACE) has a non-canonical function
in the nucleus accumbens: it degrades Met-enkephalin-Arg-Phe (MERF) and thereby regulates endogenous
opioid signaling. Conventional ACE inhibitors block the degradation of MERF, leading to an enhancement of
endogenous opioid signaling in the nucleus accumbens. This causes a selective reduction of glutamate release
onto medium spiny projection neurons that express the Drd1 dopamine receptor (D1-MSNs), which express ACE
at a higher level than other neurons. This mechanism of action has great therapeutic potential, as our preliminary
data indicate the decrease in excitatory drive to D1-MSNs can diminish the rewarding effects of fentanyl.
Previously published enzymatic assays using recombinant protein suggest that MERF is efficiently degraded by
the catalytic N-domain of ACE, though this has not been examined in brain tissue. This raises the exciting
possibility of a double-dissociation between catalytic domains of ACE that degrade angiotensin (C-domain) and
MERF (N-domain). The goal of this project is to independently evaluate the contribution of each ACE catalytic
domain to MERF degradation and endogenous opioid signaling in the nucleus accumbens, in order to generate
new domain-specific ACE inhibitors with optimized properties for treatment of opioid use disorders. We will use
mice as an experimental system to separately manipulate each catalytic domain of ACE, through a combination
of complementary genetic and pharmacological manipulations. AIM 1 is to determine which catalytic domain
of ACE degrades MERF in nucleus accumbens tissue. We will directly quantify extracellular levels of MERF
using liquid chromatography-tandem mass spectrometry, and measure excitatory synaptic transmission using
whole-cell patch-clamp recordings from nucleus accumbens neurons. AIM 2 is to determine the behavioral
impact of domain-specific ACE inhibition on fentanyl CPP and self-administration. This will build on our
preliminary experiments using non-contingent fentanyl exposure (CPP), by incorporating parallel analysis of
intravenous fentanyl self-administration on an intermittent access schedule. AIM 3 is to optimize the central
activity and drug-like properties of domain-specific ACE inhibitors. We will perform systematic chemical
iterations involving (but not limited to) prodrug and drug delivery systems, with the goal of improving permeability
across the blood-brain barrier. These experiments should result in the identification and early optimization of
compounds that inhibit degradation of MERF by ACE in the brain. This novel mechanism could form the basis
of a viable new therapeutic strategy for treating opioid use disorders.

## Key facts

- **NIH application ID:** 10512191
- **Project number:** 1R01DA056675-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Swati S More
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,771,799
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512191

## Citation

> US National Institutes of Health, RePORTER application 10512191, Domain-specific inhibition of angiotensin-converting enzyme as a therapeutic strategy for opioid use disorders (1R01DA056675-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10512191. Licensed CC0.

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