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 (9) that
is more potent than naloxone (NLX) in vitro and fully
reverses fentanyl- and carfentanil-induced ventilatory depression
and fentanyl-induced vocal cord closure in rats. Unlike naloxone,
rescue agent 9 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 9 offers a lead toward
developing such an agent.