N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes as opioid receptors probes. 1. Investigation of the phenolic hydroxyl group.

N-(3-Hydroxyphenyl)-3,8-diazabicyclooctanes represent a novel class of synthetic opioids with potent activity and a distinct pharmacological profile. The prototype of this class, atoxifent, exhibits strong opioid receptor activity while minimizing severe respiratory depression, distinguishing it from fentanyl. To gain deeper insight into ligand-receptor interactions and the factors influencing functional activity, we systematically investigated the role of the phenolic hydroxyl group. Our approach focused on (1) assessing hydrogen bonding interactions with opioid receptors, (2) modulating ionization via pKa adjustments, and (3) exploring bioisosteric replacements. In vitro assay showed that 3-amino (11), 3-cyclopropyl sulfonamide (12), and 3-carboxamido (13) derivatives retained high MOR agonist activity. Notably, 13 displayed approximately 2.4 times greater in vitro metabolic stability than atoxifent. In vivo antinociceptive studies showed that 11, 12, and 13 act as partial agonists. These findings offer valuable insight into how N-(3-hydroxyphenyl)-3,8-diazabicyclooctanes interact with opioid receptors.