基于 4-氨基苯并氮杂卓（Aba）、氮杂吲哚（Aia）和四氢异喹啉（Tic）骨架的新型多阿片配体。
Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds.
机构信息
Department of Organic Chemistry, Vrije Universiteit Brussel, B-1050 Brussels, Belgium.
出版信息
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1610-3. doi: 10.1016/j.bmcl.2010.01.055. Epub 2010 Jan 20.
Abstract
The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and balanced delta/mu antagonists, as determined by the functional [S(35)]GTPgammaS binding assay, the dimerization of potent Aia-based 'parent' ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds.
摘要
Dmt-Tic、Dmt-Aia 和 Dmt-Aba 药效团的二聚化和三聚化提供了多种配体，这些配体在体外进行了阿片受体结合和功能活性评估。尽管 Tic-和 Aba 多聚体被证明是双重且平衡的 δ/μ 拮抗剂，这是通过功能性 [S(35)]GTPγS 结合测定来确定的，但基于强效 Aia 的“母体”配体的二聚化出人意料地导致受体结合效率显著降低和非活性二聚化合物。
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1
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J Med Chem. 2009 Sep 10;52(17):5556-9. doi: 10.1021/jm900686q.
2
Design of multivalent ligand targeting G-protein-coupled receptors.
Curr Pharm Des. 2009;15(6):682-718. doi: 10.2174/138161209787315639.
3
Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.
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4
Multiple ligands in opioid research.
Protein Pept Lett. 2008;15(7):668-82. doi: 10.2174/092986608785133672.
5
Further studies on lead compounds containing the opioid pharmacophore Dmt-Tic.
J Med Chem. 2008 Aug 28;51(16):5109-17. doi: 10.1021/jm800587e. Epub 2008 Aug 5.
6
Structure-activity relationships of the dimeric analogues of endomorphin-2 with different lengths of spacers.
Protein Pept Lett. 2008;15(3):275-9. doi: 10.2174/092986608783744199.
7
Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors.
J Med Chem. 2007 Nov 1;50(22):5528-32. doi: 10.1021/jm061465o. Epub 2007 Oct 10.
8
[N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.
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9
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