Truong Phong M, Hassan Sergio A, Lee Yong-Sok, Kopajtic Theresa A, Katz Jonathan L, Chadderdon Aaron M, Traynor John R, 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 and the 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, United States.
Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States.
Bioorg Med Chem. 2017 Apr 15;25(8):2406-2422. doi: 10.1016/j.bmc.2017.02.064. Epub 2017 Mar 1.
The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and KCO to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPS) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the μ-opioid receptor (e.g., 1R,5R,9S-16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy μ-agonists (EC=0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPS assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16 was unusual, it had good affinity for the μ-OR (Ki=26.5nM) and was an efficacious μ-antagonist (Ke=29.1nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16 μ-agonist and the previously synthesized (1R,5R,9S)-(-)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(-)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.
使用溴化氰和碳酸钾改进原始的N-去甲基化程序，合成了多种N-烷基、N-芳烷基和N-环丙基烷基-9β-羟基-5-(3-羟基苯基)吗啉的对映体。测定了它们与μ-、δ-和κ-阿片受体(ORs)的结合亲和力，并对具有合理亲和力的化合物进行了功能(GTPS)测定。1R,5R,9S-对映体(1R,5R,9S)-(-)-5-(3-羟基苯基)-2-(4-硝基苯乙基)-2-氮杂双环[3.3.1]壬烷-9-醇(1R,5R,9S-16)、(1R,5R,9S)-(-)-2-肉桂基-5-(3-羟基苯基)-2-氮杂双环[3.3.1]壬烷-9-醇(1R,5R,9S-20)和(1R,5R,9S)-(-)-5-(3-羟基苯基)-2-(4-(三氟甲基)苯乙基)-2-氮杂双环[3.3.1]壬烷-9-醇(1R,5R,9S-15)对μ-阿片受体具有高亲和力(例如，1R,5R,9S-16的Ki分别为0.073、0.74和1.99nM)。1R,5R,9S-16和1R,5R,9S-15是完全、高效的μ-激动剂(EC分别为0.74和18.5nM)，在GTPS测定中，前者被发现是δ-OR的部分激动剂和κ-OR的拮抗剂，而后者是δ-OR和κ-OR的部分激动剂。1R,5R,9S-16的对映体(+)-1S,5S,9R-16不同寻常，它对μ-OR具有良好的亲和力(Ki = 26.5nM)，并且是一种有效的μ-拮抗剂(Ke = 29.1nM)。使用1R,5R,9S-16 μ-激动剂和先前合成的(1R,5R,9S)-(-)-5-(9-羟基-5-(3-羟基苯基-2-苯乙基)-2-氮杂双环[3.3.1]壬烷(1R,5R,9S-(-)-NIH 11289)对μ-OR进行了分子动力学模拟，以提供观察到的高亲和力和效力的结构基础。阐明了9β-OH和对硝基的关键作用，后者与结合腔深处的残基形成直接、持久的氢键，前者通过高度结构化的水桥与特定残基相互作用。
