U01DA051377

Development of Agents for Synthetic Opioid Overdose

Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine. It is commonly used for pain management and as an adjuvant for anesthesia. Additionally, fentanyl is considered an incapacitating agent, which means it can produce a disabling condition that persists for hours to days after exposure, such as in an unexpected chemical attack. As an opioid, fentanyl depresses the central nervous system and respiratory functions, and can be lethal due to respiratory depression. Even a few milligrams of fentanyl or other synthetic opioids can be deadly to individuals who are not tolerant to opioids.

First responders at a chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life-threatening toxicities. Currently, there are three opioid antagonists available on the market that have the potential to reverse the effects of fentanyl: naloxone, naltrexone, and nalmefene. Naloxone is the most commonly used and is approved for administration by various routes, including intravenous, intramuscular, subcutaneous, and intranasal. However, recent reports suggest that higher doses or repeated dosing of naloxone may be required to reverse fentanyl-induced respiratory depression. This highlights the urgent need for a more potent and longer-acting opioid antagonist to combat fentanyl-induced respiratory depression.

Previous studies, as well as our own preliminary results, indicate that structural modification of naltrexone can increase its potency and duration of action. Our central hypothesis is that structural modification of naltrexone will lead to novel opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure.

The specific aims of this proposal are as follows:

1. Identify opioid antagonists with enhanced pharmacodynamic and pharmacokinetic properties.
2. Determine and optimize the in vivo activity of opioid antagonists in mice, and evaluate their effectiveness in reversing the effects of fentanyl in preclinical models of antinociception, iteratively with Aim 1.
3. Determine and optimize the in vivo activity of opioid antagonists in rats, and evaluate their effectiveness in reversing the effects of fentanyl and selected analogues in preclinical models of opioid-induced locomotor and respiratory depression, iteratively with Aim 1.

The design, synthesis, and evaluation of these molecules will have a broad impact on the development of new pharmacologic probes that are designed to interact with high potency and long duration at opioid receptors. This information will facilitate the identification of safe and effective therapeutics that can rescue individuals after an acute and unexpected exposure to fentanyl and related analogues.

University Of Kentucky Research Foundation

NOT APPLICABLE

93.310 - Trans-NIH Research Support

National Institute on Drug Abuse (NIDA) [HHS - NIH]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Lexington, Kentucky 40526 United States

Single Zip Code

Countermeasures Against Chemical Threats (CounterACT): Identification of Therapeutic Lead Compounds (U01 Clinical Trial Not Allowed) (PAR-19-039)

Amendment Since initial award the total obligations have increased 195% from $459,000 to $1,353,358.