Trivedi Riya R, Luo Dan, Hessing Marissa C, Prantzalos Emily, Alilain Warren J, Turner Jill R, Prisinzano Thomas E
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40506, USA.
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.
Eur J Med Chem. 2025 Nov 15;298:117991. doi: 10.1016/j.ejmech.2025.117991. Epub 2025 Jul 23.
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.
N-(3-羟基苯基)-3,8-二氮杂双环辛烷是一类新型的合成阿片类药物，具有强大的活性和独特的药理特性。该类药物的原型阿托昔芬表现出强烈的阿片受体活性，同时将严重的呼吸抑制降至最低，这使其有别于芬太尼。为了更深入地了解配体-受体相互作用以及影响功能活性的因素，我们系统地研究了酚羟基的作用。我们的方法集中在：(1)评估与阿片受体的氢键相互作用；(2)通过调整pKa来调节离子化；(3)探索生物电子等排体替代物。体外试验表明，3-氨基（11）、3-环丙基磺酰胺（12）和3-羧酰胺（13）衍生物保留了较高的μ阿片受体激动剂活性。值得注意的是，13的体外代谢稳定性比阿托昔芬高约2.4倍。体内抗伤害感受研究表明，11、12和13作为部分激动剂起作用。这些发现为N-(3-羟基苯基)-3,8-二氮杂双环辛烷与阿片受体的相互作用提供了有价值的见解。
