Systematic Structure–Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments

Despite the availability of numerous pain medications,
the current
array of Food and Drug Administration-approved options falls short
in adequately addressing pain states for numerous patients and consequently
worsens the opioid crisis. Thus, it is imperative for basic research
to develop novel and nonaddictive pain medications. Toward addressing
this clinical goal, nalfurafine (NLF) was chosen as a lead and its
structure–activity relationship (SAR) systematically studied
through design, syntheses, and in vivo characterization
of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail
immersion assay, produced in vivo effects primarily
mediated by KOR and DOR, penetrated the blood–brain barrier,
and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these
results aid the understanding of NLF SAR and provide insights for
future endeavors in developing novel nonaddictive therapeutics to
treat pain.