Gutman Eugene S, Bow Eric, Li Fuying, Sulima Agnieszka, Kaska Sophia, Crowley Rachel, Prisinzano Thomas E, Lee Yong-Sok, Hassan Sergio A, Imler Gregory H, Deschamps Jeffrey R, Jacobson Arthur E, Rice Kenner C
Drug Design and Synthesis Section , Molecular Targets and Medications Discovery Branch , Intramural Research Program , National Institute on Drug Abuse , National Institute on Alcohol Abuse and Alcoholism , National Institutes of Health , Department of Health and Human Services , 9800 Medical Center Drive , Bethesda , MD 20892-3373 , USA . Email:
Department of Pharmaceutical Sciences , College of Pharmacy , University of Kentucky , 789 S. Limestone Street , Lexington , Kentucky 40536 , USA.
RSC Med Chem. 2020 Jun 12;11(8):896-904. doi: 10.1039/d0md00104j. eCollection 2020 Aug 1.
A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy--phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter assay and in the Tango assay. Compound (3-((1,5,9)-2-phenethyl-9-propyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), (3-((1,5,9)-9-(()-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), and (3-((1,5,9)-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol) were partial μ-agonists. Two of them had moderate efficacies ( 65%) and one had lower efficacy, and they were 5, 3, and 4 times more potent, respectively, than morphine . Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.
基于3-羟基-苯乙基-5-苯基吗啡（3-(2-苯乙基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚）C9位的三碳链，合成了一系列带有各种取代基的化合物。在福司可林诱导的cAMP积累抑制试验中，发现其中三种是μ-阿片受体激动剂，并且在PathHunter试验和Tango试验中它们根本不招募β-抑制蛋白。化合物（3-((1,5,9)-2-苯乙基-9-丙基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚）、（3-((1,5,9)-9-(()-3-羟基丙-1-烯-1-基)-2-苯乙基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚）和（3-((1,5,9)-9-(2-羟丙基)-2-苯乙基-2-氮杂双环[3.3.1]壬烷-5-基)苯酚）是部分μ-激动剂。其中两种具有中等效力（65%），一种效力较低，并且它们的效力分别比吗啡高5倍、3倍和4倍。进行了计算机模拟，以提供C9取代的5-苯基吗啡对G蛋白激活的高偏向比的分子基础。
