Development of Agents for Synthetic Opioid Overdose

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Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for the treatment of pain, as well as an adjuvant for anesthesia. It is also considered an incapacitating agent, a chemical that produces a disabling condition that persists for hours to days after exposure has occurred, such as in an unexpected chemical attack. As an opioid, fentanyl depresses the central nervous system and respiratory functions, and can be lethal by respiratory depression. Due to its high potency, ingestion of just a few milligrams of fentanyl or other synthetic opioid can be deadly to an opioid naïve individual. Furthermore, 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 potential to reverse the effects of fentanyl, namely naloxone, naltrexone, and nalmefene. The most commonly used is naloxone which is approved for administration by a variety of routes, including intravenous, intramuscular, subcutaneous and intranasal. However, recent reports suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fentanyl-induced respiratory depression. This highlights the pressing need for a more potent and longer acting opioid antagonist to combat fentanyl-induced respiratory depression. Previous studies and 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 (1) identify opioid antagonists with enhanced pharmacodynamic and pharmacokinetic properties; (2) determine and optimize the in vivo activity of opioid antagonists in mice, and for their effectiveness in reversing the effects of fentanyl in preclinical models of antinociception, iteratively with Aim 1; and (3) determine and optimize the in vivo activity of opioid antagonists in rats, and for 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, evaluation of these molecules will have a broad impact on 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 would rescue individuals after an acute and unexpected exposure to fentanyl and related analogues.