Hernandez Delmis E, Luo Dan, Prisinzano Thomas E, Negus S Stevens, Nassehi Nima, Selley Dana E, Shah Pranav, Kato Rintaro, Xu Xin, Talarico Carmine, Graziani Davide, Beccari Andrea R, Jacobson Arthur E, Rice Kenner C, Sulima Agnieszka
Department of Health and Human Services, Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, Maryland 20892-3373, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States.
ACS Chem Neurosci. 2025 Jun 4;16(11):2110-2127. doi: 10.1021/acschemneuro.5c00211. Epub 2025 May 20.
Replacement of the phenolic hydroxy in 3-((1,5,9)-2-phenethyl-9-vinyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol (), a potent efficacious MOR agonist, with an amide bioisosteric moiety provided a MOR partial agonist with morphine-like potency in the forskolin-induced cAMP accumulation assay and in the [S]GTPγS functional assay. This amide, , had superior metabolic stability in comparison to its precursor in human and mouse liver microsomes. However, in an antinociception study, an assay of pain-depressed locomotion in mice, it was found to possess shorter antinociceptive activity than its precursor. The in vitro and in vivo data enabled the characterization of amide, , as a functionally selective, low-efficacy, and low-potency MOR agonist with a relatively short duration of action in vivo. Modification of the -phenethyl substituent in gave a number of highly interesting partial agonists and the unexpectedly potent antagonist, . The results of molecular docking and binding free energy calculations for and provided details about their receptor interactions and supported their functional roles. Several analogs synthesized were found to have sufficient potency in vitro to warrant further study.
在强效有效的μ阿片受体（MOR）激动剂3-((1,5,9)-2-苯乙基-9-乙烯基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚（）中，用酰胺生物电子等排体部分取代酚羟基，得到了一种在福斯高林诱导的环磷酸腺苷（cAMP）积累试验和[S]GTPγS功能试验中具有类吗啡效力的MOR部分激动剂。与它的前体相比，这种酰胺（）在人和小鼠肝微粒体中具有更高的代谢稳定性。然而，在一项抗伤害感受研究（小鼠疼痛抑制运动试验）中，发现它的抗伤害感受活性比其前体短。体外和体内数据表明酰胺（）是一种功能选择性、低效和低效力的MOR激动剂，在体内作用持续时间相对较短。对（）中苯乙基取代基的修饰产生了许多非常有趣的部分激动剂和意外强效的拮抗剂（）。对（）和（）的分子对接和结合自由能计算结果提供了它们与受体相互作用的细节，并支持了它们的功能作用。发现合成的几种类似物在体外具有足够的效力，值得进一步研究。
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