# Pharmacological and behavioral effects of MCAM: a long-acting, μ opioid receptor antagonist for treatment of opioid overdose and opioid abuse disorder

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $461,788

## Abstract

Methocinnamox (MCAM) is a long-acting µ-opioid receptor antagonist that may have distinct advantages in the
treatment of both opioid overdose and opioid abuse disorder. We propose to evaluate MCAM using in vitro and
in vivo measures, comparing the actions of MCAM with those of the opioid antagonists naltrexone and naloxone,
that are currently used to treat abuse and overdose, respectively. We hypothesize that differences in
pharmacological properties, including binding kinetics and non-surmountablility by opioids of abuse, will
distinguish MCAM from those of the other opioid receptor antagonists. In vitro, we will compare MCAM to
naloxone for kinetics of association/dissociation, surmountability by opioid agonists (fentanyl, morphine), the
duration of antagonism (is MCAM irreversible?), and determine the pharmacological characteristics of MCAM at
multiple cellular signaling pathways. In vivo measures will be taken in rats to ascertain the duration of action and
insurmountability of MCAM in several relevant preparations. Reversal of μ opioid receptor agonist- (morphine
and fentanyl) induced respiratory depression will be evaluated using whole body plethysmography. The relative
duration of overdose protection afforded by MCAM versus naloxone will be measured in this preparation as well.
Models of protection against opioid abuse will utilize measures of the reinforcing effects of the μ opioid receptor
agonist remifentanil. The relative insurmountability and duration of action of MCAM versus naltrexone (currently
used to treat abuse) in blocking the reinforcing effects of remifentanil will be established in this preparation. The
smallest dose of MCAM that is effective when given daily in preventing the reinforcing effects of remifentanil will
provide information on the rate of delivery that would be appropriate in a sustained-release formulation of MCAM.
Comparisons will also be made of the relative ability of MCAM versus naloxone to elicit withdrawal in opioid-
dependent rats. Lastly, because current µ opioid analgesic drugs will not be effective if a long-acting antagonist
(e.g., MCAM) is used to treat abuse and/or overdose, we will assess the feasibility of peripherally-restricted
administration of kappa opioid receptor agonists for use as analgesic agents in the presence of MCAM. Activation
of peripheral kappa opioid receptors that are expressed on peripheral pain-sensing neurons can produce a level
of analgesia equivalent to that produced by a local anesthetic and therefore may be a good approach for the
treatment of pain in individuals with long-term blockade of µ opioid receptor function. Together, this work will
provide needed information about whether MCAM offers substantial advantage over naloxone and naltrexone in
blocking or preventing the actions of opioid drugs of abuse.

## Key facts

- **NIH application ID:** 9923616
- **Project number:** 5R01DA048214-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** WILLIAM P CLARKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $461,788
- **Award type:** 5
- **Project period:** 2019-05-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923616

## Citation

> US National Institutes of Health, RePORTER application 9923616, Pharmacological and behavioral effects of MCAM: a long-acting, μ opioid receptor antagonist for treatment of opioid overdose and opioid abuse disorder (5R01DA048214-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9923616. Licensed CC0.

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