# Development of Long Lasting Stable Fentanyl Antagonist to Reverse Opioid Overdose

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $234,000

## Abstract

Project Abstract
Opioid-related overdoses account for almost half of all drug overdose deaths in the United
States and cause more preventable deaths every year than car crashes. Fentanyl, a highly
potent mu opioid receptor (MOR) agonist, and its analogs (fentalogs) are increasingly found cut
into illicit drug samples, both where the primary drug of abuse is an opioid and in cases where it
is not. The prevalence of fentalogs in the illicit drug market is thought to be the primary driver of
increased opioid-related overdose deaths since 2016. The standard opioid overdose rescue
therapy, naloxone is often insufficient to reverse opioid overdoses caused by fentalog agonists
under current treatment paradigms. It has been reported that naloxone is either not potent
enough or has too short a duration of action to effectively reverse fentalog overdose and
resuscitate patients. The objective of this proposal is to design novel opioid antagonists on the
fentanyl scaffold based on previously identified fentalog antagonists and improve their
pharmacokinetic properties (limited metabolism, high blood-brain penetration, and rapid
absorption) relative to naloxone. We propose that the fentanyl scaffold is a good starting point
as fentanyl and its analogs already bind tightly to MOR and display rapid onset of action in vivo.
The overarching hypothesis is that antagonists on the fentalog scaffold will be more effective
than naloxone in blocking opioid overdose. We will explore this hypothesis in two aims: 1) we
will examine the ability of two lead fentalog antagonists to block fentanyl induced antinociception
and respiratory depression and examine their distribution and metabolism in whole animal
models and 2) design novel metabolically stable analogs which we will characterize both in vitro
and in vivo. Overall, this project will develop new fentalog antagonists for the treatment of opioid
overdose and characterize their in vitro and in vivo pharmacological properties.

## Key facts

- **NIH application ID:** 10041480
- **Project number:** 1R21DA051732-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jessica Priya Anand
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10041480

## Citation

> US National Institutes of Health, RePORTER application 10041480, Development of Long Lasting Stable Fentanyl Antagonist to Reverse Opioid Overdose (1R21DA051732-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10041480. Licensed CC0.

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