Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.
Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.
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通过 9β-羟基-5-(3-羟基苯基)吗啡烷的 N 取代调节阿片受体亲和力和功效：合成和计算机模拟研究。
DOI：
10.1016/j.bmc.2017.02.064
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发表时间：
2017
影响因子：
3.5
通讯作者：
Rice,KennerC
中科院分区：
文献类型：
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作者：
Truong,PhongM;Hassan,SergioA;Lee,Yong-Sok;Kopajtic,TheresaA;Katz,JonathanL;Chadderdon,AaronM;Traynor,JohnR;Deschamps,JeffreyR;Jacobson,ArthurE;Rice,KennerC
用溴化氰和碳酸钾对原N-脱甲基化反应进行改进，合成了多种N-烷基、N-芳烷基和N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans的对映体。测定了它们与μ-，δ-阿片受体和κ-阿片受体(ORs)的结合亲和力，并对亲和力合理的人进行了功能分析(γ35S)。1R，5R，9S-对映体(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)，和(1R，5R，9S)-(−)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol(1R，5R，9S-15)对μ-阿片受体有较高的亲和力(例如，1R，5R，9S-16：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_(50)分别为0.74和18.5nM)，前者是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、(+)-1S、5S、9R-16的对映体很少见，对μ-OR有很好的亲和力(Ki=26.5nM)，是一种有效的μ拮抗剂(Ke=129.1nM)。用1R，5R，9S-16NIH激动剂和预先合成的(1R，5R，9S)-(−)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane(1R，5R，9S-(μ)-μ11289)对−-OR进行了分子动力学模拟，为观察到的高亲和力和高效率提供了结构基础。9β-OH和对硝基的关键作用被阐明，后者与结合腔深处的残基形成直接的、持久的氢键，前者通过高结构的水桥与特定的残基相互作用。
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 K2CO3to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) 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 1.99 nM, respectively). The 1R,5R,9S-16and 1R,5R,9S-15were full, high efficacy μ-agonists (EC50= 0.74 and 18.5 nM, 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 GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16was unusual, it had good affinity for the μ-OR (Ki = 26.5 nM) and was an efficacious μ-antagonist (Ke = 29.1 nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16μ-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 thep-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.