Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and mice.
Opioid activity of spinally selective analogues of N-naphthoyl-β-naltrexamine in HEK-293 cells and mice.
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N-萘酰-β-纳曲胺脊髓选择性类似物在 HEK-293 细胞和小鼠中的阿片类活性。
DOI：
10.1021/jm200902v
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发表时间：
2012
影响因子：
7.3
通讯作者：
Portoghese,PhilipS
中科院分区：
文献类型：
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作者：
LeNaour,Morgan;Lunzer,MaryM;Powers,MikeD;Portoghese,PhilipS
以选择性mu-kappa激动剂n -萘基-β-纳曲胺1为原型配体，合成了一系列密切相关的萘类似物，研究萘部分周围的化学空间，以评价化学修饰对受体选择性的影响。合成了化合物1的9个类似物（2-10），并在表达同种和异种阿片受体的HEK-293细胞上进行了测试，并在小鼠摇尾实验中进行了测试。结果发现，该系列中结构的微小变化会导致选择性的深刻变化。引入6-氟基团可将选择性mu-kappa异聚受体激动剂转化为偏向于δ的激动剂。体内研究表明，许多配体在脊柱上比在脊柱上更有效，并且缺乏耐受性。
Using the selective mu–kappa agonist,N-naphthoyl-β-naltrexamine1, as the prototype ligand, a series of closely related naphthalene analogues were synthesized to study the chemical space around the naphthalene moiety in an effort to evaluate how receptor selectivity is affected by chemical modification. Nine analogues (2–10) of compound1were synthesized and tested on HEK-293 cells expressing homomeric and heteromeric opioid receptors, and in the mouse tail-flick assay. It was found that a small change in structure produces profound changes in selectivity in this series. This is exemplified by the discovery that introduction of a 6-fluoro group transforms1from a selective mu–kappa heteromeric receptor agonist to a delta-preferring agonist7. The in vivo studies reveal that many of the ligands are more potent spinally than supraspinally and devoid of tolerance.