Modifying naloxone to reverse fentanyl-induced overdose

Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanylinduced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.

Automated summary

Developing an effective antidote for fentanyl-induced overdose is an important medical need. In this study, a bioreversible derivative of naloxone, NX-90, was synthesized and evaluated for its ability to reverse fentanyl-induced overdose in rats. The results showed that NX-90 restored all monitored reflexes, heart rate, and respiratory rate faster than naloxone on equimolar bases when given intranasally. In addition to its improved pharmacodynamics profile, NX-90 had lower levels of circulating naloxone and demonstrated a robust release of the parent naloxone in the brain. Based on these findings, NX-90 was identified as a promising intranasal fentanyl antidote for further preclinical development.