新型含芳香四氢异喹啉取代基的二甲基酪氨酸-四氢异喹啉肽拟似物具有 κ 和 μ 阿片受体激动活性。
Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show Kappa and Mu Opioid Receptor Agonism.
机构信息
Department of Medicinal Chemistry, College of Pharmacy , University of Michigan , Ann Arbor , Michigan 48109 , United States.
Department of Pharmacology, Medical School , University of Michigan , Ann Arbor , Michigan 48109 , United States.
出版信息
ACS Chem Neurosci. 2019 Aug 21;10(8):3682-3689. doi: 10.1021/acschemneuro.9b00250. Epub 2019 Jul 1.
Abstract
The dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold was originally developed in the production of selective delta opioid receptor (DOR) antagonists. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline core of this classic opioid scaffold introduced kappa opioid receptor (KOR) agonism. Further modification of this pendant resulted in retention of KOR agonism and the addition of mu opioid receptor (MOR) partial agonism, a bifunctional profile with potential to be used in the treatment of cocaine addiction.
摘要
二甲基酪氨酸-四氢异喹啉（Dmt-Tiq）骨架最初是在选择性 δ 阿片受体（DOR）拮抗剂的生产中开发的。在该经典阿片骨架的四氢异喹啉核心上安装 7-苄基侧链，引入 κ 阿片受体（KOR）激动作用。进一步修饰该侧链，保留了 KOR 激动作用，并增加了 μ 阿片受体（MOR）部分激动作用，形成一种具有治疗可卡因成瘾潜力的双功能特征。
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3
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Br J Pharmacol. 2018 Jun;175(11):2013-2027. doi: 10.1111/bph.14148. Epub 2018 Apr 24.
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Cell. 2018 Jan 11;172(1-2):55-67.e15. doi: 10.1016/j.cell.2017.12.011. Epub 2018 Jan 4.
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Neuropharmacology. 2018 Mar 15;131:238-255. doi: 10.1016/j.neuropharm.2017.12.032. Epub 2017 Dec 20.
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