布托啡诺的单价和二价配体：连接链的特性决定了此类阿片样物质配体的亲和力和效价。
Univalent and bivalent ligands of butorphan: characteristics of the linking chain determine the affinity and potency of such opioid ligands.
作者信息
Decker Michael, Fulton Brian S, Zhang Bin, Knapp Brian I, Bidlack Jean M, Neumeyer John L
机构信息
Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.
出版信息
J Med Chem. 2009 Dec 10;52(23):7389-96. doi: 10.1021/jm900379p.
Abstract
Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the mu, delta, and kappa opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer length and structure show potent binding profiles with the most potent compound (4b), having K(i) values of 0.47 nM for both the mu and kappa opioid receptors, and 4a, having K(i) values of 0.95 and 0.62 nM for the mu and kappa receptors, respectively. Both 4a and 4b were partial agonists at the kappa and micro receptors in the [(35)S]GTPgammaS binding assay.
摘要
合成了含有酯连接体的二价吗啡喃化合物，并测定了它们对μ、δ和κ阿片受体的结合亲和力。在对水解不稳定的酯键相邻位置添加甲基可提高稳定性，同时仅部分影响结合亲和力。所得具有优化间隔长度和结构的二价配体显示出强效的结合谱，其中最有效的化合物（4b）对μ和κ阿片受体的K(i)值均为0.47 nM，而化合物4a对μ和κ受体的K(i)值分别为0.95 nM和0.62 nM。在[(35)S]GTPγS结合试验中，4a和4b在κ和μ受体上均为部分激动剂。
相似文献
1
Univalent and bivalent ligands of butorphan: characteristics of the linking chain determine the affinity and potency of such opioid ligands.布托啡诺的单价和二价配体：连接链的特性决定了此类阿片样物质配体的亲和力和效价。
J Med Chem. 2009 Dec 10;52(23):7389-96. doi: 10.1021/jm900379p.
2
Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for κ, μ, and δ opioid receptors.新型单和双价吗啡烷配体对 κ、μ 和 δ 阿片受体的合成和结合亲和力。
Bioorg Med Chem. 2011 May 1;19(9):2808-16. doi: 10.1016/j.bmc.2011.03.052. Epub 2011 Mar 26.
3
Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors.连接子取代对丁丙诺啡单价和双价配体与阿片受体结合的影响。
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1507-9. doi: 10.1016/j.bmcl.2010.01.101. Epub 2010 Jan 25.
4
Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors.新型二聚体吗啡喃类κ和μ阿片受体配体的设计与合成
J Med Chem. 2003 Nov 20;46(24):5162-70. doi: 10.1021/jm030139v.
5
High-affinity carbamate analogues of morphinan at opioid receptors.吗啡喃在阿片受体处的高亲和力氨基甲酸酯类似物。
Bioorg Med Chem Lett. 2007 Mar 15;17(6):1508-11. doi: 10.1016/j.bmcl.2007.01.013. Epub 2007 Jan 17.
6
In-vitro investigation of oxazol and urea analogues of morphinan at opioid receptors.吗啡喃的恶唑和尿素类似物在阿片受体上的体外研究。
Bioorg Med Chem. 2007 Jun 15;15(12):4106-12. doi: 10.1016/j.bmc.2007.03.076. Epub 2007 Mar 30.
7
New opioid designed multiple ligand from Dmt-Tic and morphinan pharmacophores.基于Dmt-Tic和吗啡喃药效基团设计的新型阿片样物质多配体。
J Med Chem. 2006 Sep 7;49(18):5640-3. doi: 10.1021/jm0605785.
8
Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors.在μ、δ和κ阿片受体上，含有与纳布啡、纳曲酮和纳洛酮相连的布托啡诺的二价配体的药理特性。
J Med Chem. 2007 May 3;50(9):2254-8. doi: 10.1021/jm061327z. Epub 2007 Apr 4.
9
Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors.2-取代基和 3-氨基吗啡烷类化合物的合成及阿片受体结合亲和力：μ、κ 和 δ 阿片受体的配体。
J Med Chem. 2010 Jan 14;53(1):402-18. doi: 10.1021/jm9013482.
10
Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta, and kappa opioid receptors.含有μ、δ和κ阿片受体同二聚体和异二聚体药效基团的二价配体的合成及初步体外研究。
J Med Chem. 2006 Jan 12;49(1):256-62. doi: 10.1021/jm050577x.
引用本文的文献
1
Biased, Bitopic, Opioid-Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction.具有偏向性、双靶点、阿片-肾上腺素能连接的化合物可能会提高特异性、降低剂量，并增强激动剂或拮抗剂功能，同时降低耐受性和成瘾风险。
Pharmaceuticals (Basel). 2022 Feb 10;15(2):214. doi: 10.3390/ph15020214.
2
Pharmacological Profiles of Oligomerized μ-Opioid Receptors.寡聚 μ 阿片受体的药理学特性。
Cells. 2013 Oct 11;2(4):689-714. doi: 10.3390/cells2040689.
3
A facile synthesis for novel loperamide analogs as potential μ opioid receptor agonists.一种新型洛哌丁胺类似物的简便合成方法，作为潜在的 μ 阿片受体激动剂。
Molecules. 2012 Dec 3;17(12):14288-97. doi: 10.3390/molecules171214288.
4
Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for κ, μ, and δ opioid receptors.新型单和双价吗啡烷配体对 κ、μ 和 δ 阿片受体的合成和结合亲和力。
Bioorg Med Chem. 2011 May 1;19(9):2808-16. doi: 10.1016/j.bmc.2011.03.052. Epub 2011 Mar 26.
5
Opioid bifunctional ligands from morphine and the opioid pharmacophore Dmt-Tic.吗啡和阿片类药物药效团 Dmt-Tic 的双功能阿片类配体。
Eur J Med Chem. 2011 Feb;46(2):799-803. doi: 10.1016/j.ejmech.2010.12.001. Epub 2010 Dec 8.
6
Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors.连接子取代对丁丙诺啡单价和双价配体与阿片受体结合的影响。
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1507-9. doi: 10.1016/j.bmcl.2010.01.101. Epub 2010 Jan 25.
本文引用的文献
1
Aminolysis of esters. I. Kinetics and mechanism in anhydrous doxane.酯的氨解。I. 无水二氧六环中的动力学和机理
J Am Chem Soc. 1967 Jun 1;89(12):3020-6. doi: 10.1021/ja00988a039.
2
In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: isomeric, bivalent ligands with mu/kappa agonist properties.(-)(-)MCL-144和(+)(-)MCL-193的体内特性：具有μ/κ激动剂特性的同分异构二价配体。
Neurochem Res. 2008 Oct;33(10):2142-50. doi: 10.1007/s11064-008-9752-3. Epub 2008 Jun 5.
3
Cyclopropanecarboxylic acid esters as potential prodrugs with enhanced hydrolytic stability.环丙烷羧酸酯作为具有增强水解稳定性的潜在前药。
Org Lett. 2008 Feb 7;10(3):509-11. doi: 10.1021/ol702892e. Epub 2008 Jan 9.
4
Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors.在μ、δ和κ阿片受体上，含有与纳布啡、纳曲酮和纳洛酮相连的布托啡诺的二价配体的药理特性。
J Med Chem. 2007 May 3;50(9):2254-8. doi: 10.1021/jm061327z. Epub 2007 Apr 4.
5
Kappa receptor bivalent ligands.κ受体二价配体
Curr Top Med Chem. 2007;7(4):363-73. doi: 10.2174/156802607779941251.
6
Synthesis and preliminary in vitro investigation of bivalent ligands containing homo- and heterodimeric pharmacophores at mu, delta, and kappa opioid receptors.含有μ、δ和κ阿片受体同二聚体和异二聚体药效基团的二价配体的合成及初步体外研究。
J Med Chem. 2006 Jan 12;49(1):256-62. doi: 10.1021/jm050577x.
7
Tetrabutylammonium fluoride-mediated rapid alkylation reaction in microtiter plates for the discovery of enzyme inhibitors in situ.四丁基氟化铵介导的微孔板快速烷基化反应用于原位发现酶抑制剂。
Chembiochem. 2005 Dec;6(12):2176-80. doi: 10.1002/cbic.200500295.
8
Design and synthesis of novel dimeric morphinan ligands for kappa and micro opioid receptors.新型二聚体吗啡喃类κ和μ阿片受体配体的设计与合成
J Med Chem. 2003 Nov 20;46(24):5162-70. doi: 10.1021/jm030139v.
9
Several delta-opioid receptor ligands display no subtype selectivity to the human delta-opioid receptor.几种δ-阿片受体配体对人δ-阿片受体没有亚型选择性。
Eur J Pharmacol. 2002 Sep 20;451(3):257-64. doi: 10.1016/s0014-2999(02)02241-0.
10
Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan.混合κ激动剂和μ激动剂/拮抗剂作为可卡因滥用的潜在药物治疗方法：吗啡喃N-取代衍生物的合成及阿片受体结合亲和力
Bioorg Med Chem Lett. 2001 Oct 22;11(20):2735-40. doi: 10.1016/s0960-894x(01)00543-1.
Zotero 插件