# A novel opioid receptor antagonist for treating abuse and overdose

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $492,438

## Abstract

ABSTRACT
Deaths from opioid overdose continue to rise; from 2015-2016, there was a 28% increase in the number of fatal
overdoses. Fentanyl derivatives are inexpensive, easy to synthesize, potent, and marketed to unsuspecting
abusers as heroin or other drugs. Moreover, the effects of fentanyl derivatives are reportedly more difficult to
reverse with naloxone, compared with reversal of heroin. Pharmacotherapies for opioid abuse include the µ
opioid receptor agonists methadone and buprenorphine that are effective in many patients, although both drugs
have limitations, including diversion and abuse, and they can have serious unwanted effects, including
respiratory depression and death. The opioid receptor antagonists naltrexone and naloxone avoid the abuse
liability and adverse effects of methadone and buprenorphine; however, short durations of action and
surmountability limit their effectiveness. A medication with a longer duration of action that prevents and
reverses the effects of opioids in a manner that is not surmounted by increasing doses of agonist could improve
significantly treatment of abuse and save lives by providing insurmountable extended protection after rescue
from overdose. Our pilot studies in monkeys show that the pseudoirreversible, µ opioid receptor selective
antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for
remifentanil in a food/drug choice procedure, and reverses as well as protects against respiratory depression by
heroin, with a single injection being effective for a week or longer. Proposed studies build on these compelling
data and examine the long-term antagonist properties and the pharmacokinetics of MCAM in combination with
commonly abuse opioids, including ultra-potent fentanyl analogs. MCAM is hypothesized to be better than
naloxone and naltrexone in reversing and preventing the effects of opioid receptor agonists and, in particular,
high efficacy agonists that exert behavioral effects when occupying relatively few opioid receptors. Its
pseudoirreversible binding is expected to make antagonism by MCAM more difficult to surmount and to provide
longer antagonist action than the currently used opioid receptor antagonists. Aim 1 will characterize long-term
antagonism of heroin self-administration by MCAM in a food/drug choice procedure. Aim 2 will examine the
ability of MCAM to antagonize the positive reinforcing and respiratory depressant effects of fentanyl and ultra-
potent analogs alone and in mixtures with heroin or cocaine. Aim 3 will characterize the pharmacokinetic profile
of MCAM, heroin, fentanyl and its derivatives, and cocaine, alone and in mixtures. Using a highly translatable
species, this project will examine a novel opioid receptor antagonist that has the potential to save lives by
preventing and reversing the adverse, and often lethal, effects of opioids. The availability of another safe,
effective, and long-acting treatment could be advantageous f...

## Key facts

- **NIH application ID:** 10353379
- **Project number:** 5R01DA048417-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** CHARLES P FRANCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,438
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353379

## Citation

> US National Institutes of Health, RePORTER application 10353379, A novel opioid receptor antagonist for treating abuse and overdose (5R01DA048417-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10353379. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*