ABSTRACT
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 fentanyl-induced 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.
Subject(s)
Fentanyl , Naloxone , Animals , Heart Rate , RatsABSTRACT
Developing non-addictive and safer opioids for pain management is unmet medical need. Among a number of bioreversible derivatives of Nalbuphine - an equipotent to morphine opioid without serious side effects - NB-33 was identified in silico and confirmed in vivo as a superior analgesic agent. Apart from enhanced pharmacodynamics profile, NB-33 outperformed the parent compound on equimolar bases in cold ethanol tail-flick and mechanical models of pain in rats. With no ß-arrestin engagement liability, good stability in simulated gastro-intestinal fluid and slow release of Nalbuphine by plasma NB-33 is being developed as an oral and safer alternative of its parent drug.
