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

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

  • Eur J Med Chem. 2025 Nov 15:298:117991. doi: 10.1016/j.ejmech.2025.117991.
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

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40506, USA.
  • 2 Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40506, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40506, USA.
  • 3 Spinal Cord and Brain Injury Research Center (SCoBIRC), College of Medicine, University of Kentucky, Lexington, KY, 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA.
  • 4 Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40506, USA; Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY, 40506, USA. Electronic address: prisinzano@uky.edu.
PMID: 40730064 DOI: 10.1016/j.ejmech.2025.117991
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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