Characterization of a Potential KOR/DOR Dual Agonist with No Apparent Abuse Liability via a Complementary Structure–Activity Relationship Study on Nalfurafine Analogues

Discovery of analgesics void of abuse liability is critical
to
battle the opioid crisis in the United States. Among many strategies
to achieve this goal, targeting more than one opioid receptor seems
promising to minimize this unwanted side effect while achieving a
reasonable therapeutic profile. In the process of understanding the
structure–activity relationship of nalfurafine, we identified
a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta
opioid receptor agonist with minimum abuse liability. Further characterizations,
including primary in vitro ADMET studies (hERG toxicity, plasma protein
binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic
and toxicity profiling (time course, abuse liability, tolerance, withdrawal,
respiratory depression, body weight, and locomotor activity) further
confirmed NMF as a promising drug candidate for future development.