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. 2025 Nov 15:298:117991.
doi: 10.1016/j.ejmech.2025.117991. Epub 2025 Jul 23.

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

Riya R Trivedi  1 , Dan Luo  2 , Marissa C Hessing  1 , Emily Prantzalos  1 , Warren J Alilain  3 , Jill R Turner  1 , Thomas E Prisinzano  4
Affiliations

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

Riya R Trivedi et al. Eur J Med Chem. .

Abstract

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.

Keywords: Antinociceptive activity; Functional selectivity; In vitro metabolism; MOR agonist.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas E. Prisinzano reports financial support was provided by National Institute on Drug Abuse. Thomas E. Prisinzano has patent licensed to Bluegrass Pharmaceuticals. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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