Li Ennian, Reda Ahmed, Ma Hongguang, Woodard Samuel, Gillespie James C, Selley Dana E, Dewey William L, Pagare Piyusha P, Zhang Yan
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University 800 E Leigh Street Richmond Virginia 23298 USA
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University 410 North 12th Street Richmond Virginia 23298 USA.
RSC Chem Biol. 2025 May 5. doi: 10.1039/d5cb00036j.
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.
我们之前鉴定出NBF（C6位为β构型）及其6α异构体为μ阿片受体（MOR）拮抗剂。为了探究环氧吗啡喃环C6构型对其MOR功能的影响，合成了五对在苯并呋喃环3'-位带有取代基且兼具6α和6β构型的NBF衍生物。 研究表明，携带苯基和4-吡啶取代基的化合物保持其拮抗特性，与C6构型无关。具有6α构型的卤素和甲基取代基仍为MOR拮抗剂，而其6β异构体则转变为MOR激动剂。分子模拟研究表明，C6构型和结构修饰可能共同决定苯并呋喃环的取向，导致MOR结合口袋内构象保留或转变。这些结果共同有助于理解NBF的构效关系（SAR），并为MOR的功能转化提供见解，支持未来开发新型MOR配体的努力。
