Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity
Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity
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DOI：
10.1021/acs.jmedchem.5b01402
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发表时间：
2016-02-11
影响因子：
7.3
通讯作者：
Ladds, Graham
中科院分区：
文献类型：
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作者：
Knight, Anthony;Hemmings, Jennifer L.;Ladds, Graham
合成了一系列N-6-双环和N-6-（2-羟基）-环戊基腺苷衍生物作为新型A（1）R激动剂，并利用简单的酵母筛选平台评估了它们的A（1）R/A（2）R选择性。我们观察到，通过N-6-金刚烷基取代与5 ′-N-乙基甲酰胺基或5 ′-羟甲基的组合获得了最具选择性的高效力配体。此外，我们确定5 '-（2-氟）噻吩衍生物尽管显示出与A（1）R的相互作用，但都不能产生信号应答。还在哺乳动物细胞中测试了一些选定的化合物对A（1）R和A（3）R的作用，揭示其中四种化合物完全是A（1）R选择性激动剂。通过使用计算机同源性建模和配体对接，我们提供了深入了解他们的识别和激活的A（1）R的机制。我们相信，鉴于腺苷受体亚型的广泛组织分布，但对比信号传导谱，这些化合物可能具有治疗潜力。
A series of N-6-bicyclic and N-6-(2-hydroxy)-cyclopentyl derivatives of adenosine were synthesized as novel A(1)R agonists and their A(1)R/A(2)R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N-6-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A(1)R. Some selected compounds were also tested on A(1)R and A(3)R in mammalian cells revealing that four of them are entirely A(1)R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A(1)R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.