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Design, Synthesis, and Biological Evaluation of Bivalent Ligands Targeting Dopamine D2‐Like Receptors and the μ‐Opioid Receptor
ChemMedChem ( IF 3.4 ) Pub Date : 2018-04-16 , DOI: 10.1002/cmdc.201700787
Mingcheng Qian 1, 2 , Lakshmi Vasudevan 2 , Jelle Huysentruyt 2 , Martijn D. P. Risseeuw 1 , Christophe Stove 2 , Patrick M. L. Vanderheyden 3 , Kathleen Van Craenenbroeck 2 , Serge Van Calenbergh 1
Affiliation  

Currently, there is mounting evidence that intermolecular receptor–receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful as molecular probes for confirming and targeting heteromeric receptors. This report describes the design and synthesis of novel heterobivalent ligands for dopamine D2‐like receptors (D2‐likeR) and the μ‐opioid receptor (μOR) and their evaluation using ligand binding and functional assays. Interestingly, we identified a potent bivalent ligand that contains a short 18‐atom linker and combines good potency with high efficacy both in β‐arrestin 2 recruitment for μOR and MAPK‐P for D4R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D4R–μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D4R–μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D4R and μOR.

中文翻译:

针对多巴胺D2类受体和μ阿片受体的二价配体的设计,合成和生物学评估

当前,越来越多的证据表明分子间受体之间的相互作用可能会导致受体识别,药理学和信号传导发生改变。异二价配体已被证明可用于确认和靶向异聚受体的分子探针。本报告介绍了多巴胺D 2样受体(D 2 likeR)和μ阿片受体(μOR)的新型异价配体的设计和合成,以及使用配体结合和功能测定进行的评估。有趣的是,我们确定了一种有效的二价配体,该配体包含一个短的18原子接头,并且在β-arrestin2募集μOR和MAPK-P募集D 4方面都具有良好的效能和高效能R.此外,该化合物的特征是D 4 R–μOR异二聚体的双相竞争结合曲线,表明是二价结合模式。由于该化合物可能桥接了D 4 R–μOR异二聚体,因此可以用作进一步研究D 4 R与μOR相互作用的药理学工具。
更新日期:2018-04-16
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