14 - O - 杂环取代的纳曲酮衍生物作为非肽类μ阿片受体选择性拮抗剂：设计、合成及生物学研究
14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: design, synthesis, and biological studies.
作者信息
Li Guo, Aschenbach Lindsey C K, He Hengjun, Selley Dana E, Zhang Yan
机构信息
Department of Medicinal Chemistry, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298-0613, USA.
出版信息
Bioorg Med Chem Lett. 2009 Mar 15;19(6):1825-9. doi: 10.1016/j.bmcl.2008.12.093. Epub 2008 Dec 29.
Abstract
Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative 'address' domain in the extracellular loops of the mu opioid receptor.
摘要
μ阿片受体拮抗剂具有临床应用价值且是重要的研究工具。为开发非肽类且高度选择性的μ阿片受体拮抗剂，设计、合成并评估了一系列14 - O - 杂环取代的纳曲酮衍生物。这些化合物对μ阿片受体表现出纳摩尔以下至纳摩尔级别的结合亲和力。其中，化合物1对μ阿片受体相对于δ和κ受体表现出最高的选择性。这些结果提示了μ阿片受体细胞外环中一个替代性的“作用位点”结构域。
相似文献
1
14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: design, synthesis, and biological studies.14 - O - 杂环取代的纳曲酮衍生物作为非肽类μ阿片受体选择性拮抗剂：设计、合成及生物学研究
Bioorg Med Chem Lett. 2009 Mar 15;19(6):1825-9. doi: 10.1016/j.bmcl.2008.12.093. Epub 2008 Dec 29.
2
Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety.吲哚苯部分被取代的纳曲吲哚类似物的合成、阿片受体结合及生物活性测定。
J Med Chem. 1998 Jul 16;41(15):2872-81. doi: 10.1021/jm980083i.
3
Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: application of the 'message-address' concept in development of mu opioid receptor selective antagonists.通过在阿片受体晶体结构和定点突变研究中对接来研究 6α-和 6β-N-杂环取代的纳曲胺衍生物的结合模式：“信息-地址”概念在开发μ阿片受体选择性拮抗剂中的应用。
Bioorg Med Chem. 2013 Nov 1;21(21):6405-13. doi: 10.1016/j.bmc.2013.08.042. Epub 2013 Sep 4.
4
Investigation of the selectivity of oxymorphone- and naltrexone-derived ligands via site-directed mutagenesis of opioid receptors: exploring the "address" recognition locus.通过阿片受体的定点诱变研究羟吗啡酮和纳曲酮衍生配体的选择性：探索“地址”识别位点。
J Med Chem. 2001 Mar 15;44(6):857-62. doi: 10.1021/jm000381r.
5
Characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives as novel leads to development of mu opioid receptor selective antagonists.6α-和 6β-N-杂环取代的纳曲胺衍生物的特征作为开发μ阿片受体选择性拮抗剂的新先导物。
ACS Chem Neurosci. 2011 Jul 20;2(7):346-51. doi: 10.1021/cn2000348. Epub 2011 May 6.
6
Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.6α-和6β-N-杂环取代纳曲胺衍生物作为μ阿片受体选择性拮抗剂的设计、合成及生物学评价
J Med Chem. 2009 Mar 12;52(5):1416-27. doi: 10.1021/jm801272c.
7
3D-QSAR comparative molecular field analysis on opioid receptor antagonists: pooling data from different studies.阿片受体拮抗剂的3D-QSAR比较分子场分析：整合来自不同研究的数据
J Med Chem. 2005 Mar 10;48(5):1620-9. doi: 10.1021/jm049117e.
8
N-Cyclohexylethyl-N-noroxymorphindole: a mu-opioid preferring analogue of naltrindole.N-环己基乙基-N-去甲羟吗啡吲哚：一种对μ阿片受体具有选择性的纳曲吲哚类似物。
Bioorg Med Chem Lett. 2000 Nov 6;10(21):2449-51. doi: 10.1016/s0960-894x(00)00479-0.
9
Design of peptidomimetic delta opioid receptor antagonists using the message-address concept.运用信息-位点概念设计肽模拟物δ阿片受体拮抗剂
J Med Chem. 1990 Jun;33(6):1714-20. doi: 10.1021/jm00168a028.
10
Characterization of BU09059: a novel potent selective κ-receptor antagonist.新型强效选择性κ受体拮抗剂BU09059的特性研究
ACS Chem Neurosci. 2014 Mar 19;5(3):177-84. doi: 10.1021/cn4001507. Epub 2014 Jan 28.
引用本文的文献
1
Exploring substitution effects on the potential dominant conformations of NBF derivatives leading to functional conversion at the mu opioid receptor.探索NBF衍生物潜在优势构象上的取代效应，这些效应导致μ阿片受体的功能转换。
RSC Chem Biol. 2025 May 5. doi: 10.1039/d5cb00036j.
2
Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.纳曲酮类似物用于开发潜在非成瘾性疼痛管理治疗的系统构效关系研究
J Med Chem. 2024 Jun 13;67(11):9552-9574. doi: 10.1021/acs.jmedchem.4c00646. Epub 2024 May 30.
3
Verifying the role of 3-hydroxy of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[(4'-pyridyl) carboxamido]morphinan derivatives via their binding affinity and selectivity profiles on opioid receptors.通过其在阿片受体上的结合亲和力和选择性特征来验证 17-环丙甲基-4,5α-环氧-3,14β-二羟基-6β-[(4'-吡啶基)羧酰胺基]吗啡烷衍生物的 3-羟基的作用。
Bioorg Chem. 2021 Apr;109:104702. doi: 10.1016/j.bioorg.2021.104702. Epub 2021 Feb 9.
4
Mechanisms of QT prolongation by buprenorphine cannot be explained by direct hERG channel block.丁丙诺啡引起 QT 间期延长的机制不能用直接阻断 hERG 通道来解释。
PLoS One. 2020 Nov 6;15(11):e0241362. doi: 10.1371/journal.pone.0241362. eCollection 2020.
5
Synthesis, Biological Evaluation, and SAR Studies of 14β-phenylacetyl Substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones Derivatives: Ligands With Mixed NOP and Opioid Receptor Profile.14β-苯乙酰基取代的17-环丙基甲基-7,8-二氢去甲羟吗啡酮衍生物的合成、生物学评价及构效关系研究：具有混合NOP和阿片受体特征的配体
Front Psychiatry. 2018 Sep 19;9:430. doi: 10.3389/fpsyt.2018.00430. eCollection 2018.
6
6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand.6β-N-杂环取代的纳曲胺衍生物 BNAP：一种外周选择性混合 MOR/KOR 配体。
ACS Chem Neurosci. 2016 Aug 17;7(8):1120-9. doi: 10.1021/acschemneuro.6b00075. Epub 2016 Jun 15.
7
Design, synthesis, and biological evaluation of 14-heteroaromatic-substituted naltrexone derivatives: pharmacological profile switch from mu opioid receptor selectivity to mu/kappa opioid receptor dual selectivity.14-杂芳基取代纳曲酮衍生物的设计、合成及生物评价：从μ阿片受体选择性到μ/κ阿片受体双重选择性的药理学特性转换。
J Med Chem. 2013 Nov 27;56(22):9156-69. doi: 10.1021/jm4012214. Epub 2013 Nov 7.
8
Opioid receptor selectivity profile change via isosterism for 14-O-substituted naltrexone derivatives.通过 14-O-取代纳曲酮衍生物的等排体改变阿片受体选择性特征。
Bioorg Med Chem Lett. 2013 Jul 1;23(13):3719-22. doi: 10.1016/j.bmcl.2013.05.027. Epub 2013 May 16.
9
14-Alkoxy- and 14-acyloxypyridomorphinans: μ agonist/δ antagonist opioid analgesics with diminished tolerance and dependence side effects.14-烷氧基-和 14-酰氧基吡啶并吗啡烷类：具有降低的耐受性和依赖性副作用的 μ 激动剂/δ 拮抗剂阿片类镇痛药。
J Med Chem. 2012 Oct 11;55(19):8350-63. doi: 10.1021/jm300686p. Epub 2012 Sep 27.
10
Most recent developments and modifications of 14-alkylamino and 14-alkoxy-4,5-epoxymorphinan derivatives.14-烷基氨基和 14-烷氧基-4,5-环氧吗啡烷衍生物的最新发展和修饰。
Mini Rev Med Chem. 2011 Oct;11(12):1002-8. doi: 10.2174/138955711797247752.
本文引用的文献
1
Structure of a beta1-adrenergic G-protein-coupled receptor.β1-肾上腺素能G蛋白偶联受体的结构
Nature. 2008 Jul 24;454(7203):486-91. doi: 10.1038/nature07101. Epub 2008 Jun 25.
2
Crystal structure of the ligand-free G-protein-coupled receptor opsin.无配体G蛋白偶联受体视蛋白的晶体结构。
Nature. 2008 Jul 10;454(7201):183-7. doi: 10.1038/nature07063. Epub 2008 Jun 18.
3
A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor.人β2-肾上腺素能受体2.8埃的结构确定了一个特定的胆固醇结合位点。
Structure. 2008 Jun;16(6):897-905. doi: 10.1016/j.str.2008.05.001.
4
High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.一种工程化人β2-肾上腺素能G蛋白偶联受体的高分辨率晶体结构
Science. 2007 Nov 23;318(5854):1258-65. doi: 10.1126/science.1150577. Epub 2007 Oct 25.
5
GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function.G蛋白偶联受体工程为β2肾上腺素能受体功能带来了高分辨率的结构见解。
Science. 2007 Nov 23;318(5854):1266-73. doi: 10.1126/science.1150609. Epub 2007 Oct 25.
6
Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.人β2肾上腺素能G蛋白偶联受体的晶体结构
Nature. 2007 Nov 15;450(7168):383-7. doi: 10.1038/nature06325. Epub 2007 Oct 21.
7
Mu opioid receptor antagonists: recent developments.μ阿片受体拮抗剂：最新进展
ChemMedChem. 2007 Nov;2(11):1552-70. doi: 10.1002/cmdc.200700143.
8
Targeting HIV-1 through molecular modeling and docking studies of CXCR4: leads for therapeutic development.通过CXCR4的分子建模和对接研究靶向HIV-1：治疗开发的线索
Chem Biol Drug Des. 2007 Mar;69(3):191-203. doi: 10.1111/j.1747-0285.2007.00478.x.
9
Crystal structure of a photoactivated deprotonated intermediate of rhodopsin.视紫红质光激活去质子化中间体的晶体结构。
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16123-8. doi: 10.1073/pnas.0608022103. Epub 2006 Oct 23.
10
Ligand-supported homology modeling of the human angiotensin II type 1 (AT(1)) receptor: insights into the molecular determinants of telmisartan binding.人血管紧张素II 1型（AT(1)）受体的配体支持同源性建模：对替米沙坦结合分子决定因素的见解。
Proteins. 2006 Dec 1;65(4):824-42. doi: 10.1002/prot.21196.
Zotero 插件