Exploring substitution effects on the potential dominant conformations of NBF derivatives leading to functional conversion at the mu opioid receptor.

We previously identified NBF (β-configuration at C6) and its 6α-counterpart as mu opioid receptor (MOR) antagonists. To explore the effect of C6 conformation of the epoxymorphinan ring on their MOR function, five pairs of NBF derivatives bearing both 6α and 6β configurations with substitutions on the 3'-position of the benzofuran ring were synthesized. and studies demonstrated that compounds carrying phenyl and 4-pyridine substituents retained their antagonistic properties independent of the C6 configuration. Halogen and methyl substituents with the 6α-configuration remained as MOR antagonists, while their 6β-counterparts switched to MOR agonists. Molecular modeling studies indicated that the C6 configuration and structural modification may collectively decide the orientation of the benzofuran ring, leading to conformation retention or a switch within the MOR binding pocket. These results together aid the understanding of the NBF structure-activity relationship (SAR) and provide insights for functional conversion at the MOR, supporting future endeavors to develop novel MOR ligands.