Suppr超能文献

构象受限的阿片样物质配体：Dmt-Aba和Dmt-Aia与Dmt-Tic支架的比较

Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.

作者信息

Ballet Steven, Feytens Debby, Wachter Rien De, Vlaeminck Magali De, Marczak Ewa D, Salvadori Severo, Graaf Chris de, Rognan Didier, Negri Lucia, Lattanzi Roberta, Lazarus Lawrence H, Tourwé Dirk, Balboni Gianfranco

机构信息

Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.

出版信息

Bioorg Med Chem Lett. 2009 Jan 15;19(2):433-7. doi: 10.1016/j.bmcl.2008.11.051. Epub 2008 Nov 19.

DOI:10.1016/j.bmcl.2008.11.051
PMID:19062273
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2742322/
Abstract

Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent mu-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.

摘要

在阿片类药物Dmt-Tic-Gly-NH-Bn支架中，用4-氨基-1,2,4,5-四氢吲哚并[2,3-c]氮杂环庚-3-酮（Aia）和4-氨基-1,2,4,5-四氢-2-苯并氮杂环庚-3-酮（Aba）支架取代受限的苯丙氨酸类似物1,2,3,4-四氢异喹啉-3-羧酸（Tic），已导致发现新型强效μ-选择性激动剂（结构5和12）以及强效和选择性δ-阿片受体拮抗剂（结构9和15）。在研究的小肽模拟模板中，立体化学和N端N,N-二甲基化均被证明是影响阿片受体选择性和功能生物活性的关键因素。除了体外药理学评估外，还构建了Dmt-Tic和Dmt-Aba类似物的自动对接模型，以便对观察到的构效关系数据进行合理化分析。

相似文献

1
Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.
Bioorg Med Chem Lett. 2009 Jan 15;19(2):433-7. doi: 10.1016/j.bmcl.2008.11.051. Epub 2008 Nov 19.
2
Synthesis, biological evaluation, and automated docking of constrained analogues of the opioid peptide H-Dmt-D-Ala-Phe-Gly-NH₂ using the 4- or 5-methyl substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold.
J Med Chem. 2011 Oct 13;54(19):6538-47. doi: 10.1021/jm2003574. Epub 2011 Sep 14.
3
Evaluation of the Dmt-Tic pharmacophore: conversion of a potent delta-opioid receptor antagonist into a potent delta agonist and ligands with mixed properties.
J Med Chem. 2002 Jan 31;45(3):713-20. doi: 10.1021/jm010449i.
4
Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary delta opioid antagonist activity.
J Med Chem. 1997 Sep 12;40(19):3100-8. doi: 10.1021/jm9607663.
5
Bioactivity of new mu and delta opioid peptides.
Med Chem. 2007 Sep;3(5):480-7. doi: 10.2174/157340607781745429.
6
Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1610-3. doi: 10.1016/j.bmcl.2010.01.055. Epub 2010 Jan 20.
7
N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile.
Bioorg Med Chem Lett. 2013 Sep 15;23(18):5082-5. doi: 10.1016/j.bmcl.2013.07.036. Epub 2013 Jul 23.
8
Effect of lysine at C-terminus of the Dmt-Tic opioid pharmacophore.
J Med Chem. 2006 Sep 7;49(18):5610-7. doi: 10.1021/jm060741w.
9
Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C-terminus endow delta antagonists to manifest mu agonism or mu antagonism.
J Med Chem. 1999 Dec 2;42(24):5010-9. doi: 10.1021/jm990165m.
10
Crystal structures of dipeptides containing the Dmt-Tic pharmacophore.
J Med Chem. 2002 Dec 5;45(25):5506-13. doi: 10.1021/jm020330p.

引用本文的文献

1
Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery.
Biomolecules. 2022 Sep 5;12(9):1241. doi: 10.3390/biom12091241.
2
Conformational Changes in Tyrosine 11 of Neurotensin Are Required to Activate the Neurotensin Receptor 1.
ACS Pharmacol Transl Sci. 2020 Apr 29;3(4):690-705. doi: 10.1021/acsptsci.0c00026. eCollection 2020 Aug 14.
3
Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands.
ACS Omega. 2019 Oct 9;4(17):17457-17476. doi: 10.1021/acsomega.9b02244. eCollection 2019 Oct 22.
4
Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.
ACS Med Chem Lett. 2015 Oct 31;6(12):1209-14. doi: 10.1021/acsmedchemlett.5b00359. eCollection 2015 Dec 10.
5
Structural basis for bifunctional peptide recognition at human δ-opioid receptor.
Nat Struct Mol Biol. 2015 Mar;22(3):265-8. doi: 10.1038/nsmb.2965. Epub 2015 Feb 16.
6
Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics.
Eur J Med Chem. 2015 Mar 6;92:64-77. doi: 10.1016/j.ejmech.2014.12.033. Epub 2014 Dec 19.
7
One-pot isomerization-cross metathesis-reduction (ICMR) synthesis of lipophilic tetrapeptides.
ACS Comb Sci. 2014 Jul 14;16(7):342-51. doi: 10.1021/co500020a. Epub 2014 Jun 18.
8
Synthesis, pharmacological evaluation and conformational investigation of endomorphin-2 hybrid analogues.
Mol Divers. 2013 Feb;17(1):19-31. doi: 10.1007/s11030-012-9399-5. Epub 2012 Nov 4.
9
Variation of the net charge, lipophilicity, and side chain flexibility in Dmt(1)-DALDA: Effect on Opioid Activity and Biodistribution.
J Med Chem. 2012 Nov 26;55(22):9549-61. doi: 10.1021/jm3008079. Epub 2012 Nov 12.
10
Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist.
J Med Chem. 2011 Apr 14;54(7):2467-76. doi: 10.1021/jm1016285. Epub 2011 Mar 17.

本文引用的文献

1
Synthesis and pharmacological characterization of a novel, highly potent, peptidomimetic delta-opioid radioantagonist, [3H]Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH.
Neuropeptides. 2008 Feb;42(1):57-67. doi: 10.1016/j.npep.2007.10.003.
2
Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening.
Proteins. 2008 May 1;71(2):599-620. doi: 10.1002/prot.21724.
3
High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor.
Science. 2007 Nov 23;318(5854):1258-65. doi: 10.1126/science.1150577. Epub 2007 Oct 25.
4
New sst4/5-selective somatostatin peptidomimetics based on a constrained tryptophan scaffold.
J Med Chem. 2007 Jul 12;50(14):3397-401. doi: 10.1021/jm070246f. Epub 2007 Jun 9.
5
Surflex-Dock 2.1: robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search.
J Comput Aided Mol Des. 2007 May;21(5):281-306. doi: 10.1007/s10822-007-9114-2. Epub 2007 Mar 27.
6
Optimizing fragment and scaffold docking by use of molecular interaction fingerprints.
J Chem Inf Model. 2007 Jan-Feb;47(1):195-207. doi: 10.1021/ci600342e.
7
Beta-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent delta opioid antagonists.
J Med Chem. 2007 Jan 25;50(2):328-33. doi: 10.1021/jm060721u.
8
New 2',6'-dimethyl-L-tyrosine (Dmt) opioid peptidomimetics based on the Aba-Gly scaffold. Development of unique mu-opioid receptor ligands.
J Med Chem. 2006 Jun 29;49(13):3990-3. doi: 10.1021/jm0603264.
9
Opioid peptide-derived analgesics.
AAPS J. 2005 Oct 14;7(3):E560-5. doi: 10.1208/aapsj070356.
10
Complex of an active mu-opioid receptor with a cyclic peptide agonist modeled from experimental constraints.
Biochemistry. 2004 Dec 21;43(50):15796-810. doi: 10.1021/bi048413q.

文献AI研究员

20分钟写一篇综述，助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型，支持多种主流文档格式。

立即体验