Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)­carboxamido]­morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands

μ
opioid receptor (MOR) agonists have been widely applied for treating
moderate to severe pain. However, numerous adverse effects have been
associated with their application, including opioid-induced constipation
(OIC), respiratory depression, and addiction. On the basis of previous
work in our laboratory, NAP, a 6β-N-4′-pyridyl
substituted naltrexamine derivative, was identified as a peripheral
MOR antagonist that may be used to treat OIC. To further explore its
structure–activity relationship, a new series of NAP derivatives
were designed, synthesized, and biologically evaluated. Among these
derivatives, NFP and NYP significantly antagonized the antinociception
effect of morphine. Whereas NAP acted mainly peripherally, its derivatives
NFP and NYP actually can act centrally. Furthermore, NFP produced
significantly lesser withdrawal symptoms than naloxone at similar
doses. These results suggest that NFP has the potential to be a lead
compound to treat opioid abuse and addiction.