Searching for Synthetic Opioid Rescue Agents. 2: Identification of an Ultra-Potent Synthetic Opioid Rescue Agent

Ultrapotent synthetic opioids (UPSO) have become increasingly prevalent today, from being implicated in a mass casualty event to contaminating illicit drug supply across the country. These UPSOs are different than semisynthetic and naturally derived opioids, in the sense that UPSOs have a much greater ability to cause opioid-induced respiratory depression (OIRD) and wooden chest syndrome (WCS), two medical phenomena that are essential in the lethality of UPS opioids. Here, we report the identification of a potential rescue agent (<b>9</b>) that is more potent than naloxone (NLX) <i>in vitro</i> and fully reverses fentanyl- and carfentanil-induced ventilatory depression and fentanyl-induced vocal cord closure in rats. Unlike naloxone, rescue agent <b>9</b> increases minute ventilation above normal in fentanyl- or carfentanil-treated rats and appears to have limited brain penetrance. Targeting peripheral opioid receptors offers a new strategy for reversing OIRD, and <b>9</b> offers a lead toward developing such an agent.