Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity

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• 作者：Anthony Knight ; Jennifer L. Hemmings ; Ian Winfield ; Michele Leuenberger ; Eugenia Frattini ; Bruno G. Frenguelli ; Simon J. Dowell ; Martin Lochner ; Graham Ladds
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：947-964
• 全文大小：905K
• ISSN：1520-4804

文摘

A series of N⁶-bicyclic and N⁶-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A₁R agonists and their A₁R/A₂R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N⁶-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 A₁R. Some selected compounds were also tested on A₁R and A₃R in mammalian cells revealing that four of them are entirely A₁R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A₁R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.