Photomodulation of G Protein-Coupled Adenosine Receptors by a Novel Light-Switchable Ligand

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• 作者：Mar铆a Isabel Bahamonde ; Jaume Taura ; Silvia Paoletta ; Andrei A. Gakh ; Saibal Chakraborty ; Jordi Hernando ; V铆ctor Fern谩ndez-Due帽as ; Kenneth A. Jacobson ; Pau Gorostiza ; Francisco Ciruela
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：October 15, 2014
• 年：2014
• 卷：25
• 期：10
• 页码：1847-1854
• 全文大小：434K
• ISSN：1520-4812

文摘

The adenosinergic system operates through G protein-coupled adenosine receptors, which have become promising therapeutic targets for a wide range of pathological conditions. However, the ubiquity of adenosine receptors and the eventual lack of selectivity of adenosine-based drugs have frequently diminished their therapeutic potential. Accordingly, here we aimed to develop a new generation of light-switchable adenosine receptor ligands that change their intrinsic activity upon irradiation, thus allowing the spatiotemporal control of receptor functioning (i.e., receptor activation/inactivation dependent on location and timing). Therefore, we synthesized an orthosteric, photoisomerizable, and nonselective adenosine receptor agonist, nucleoside derivative MRS5543 containing an aryl diazo linkage on the N⁶ substituent, which in the dark (relaxed isomer) behaved as a full adenosine A₃ receptor (A₃R) and partial adenosine A_2A receptor (A_2AR) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full A₃R agonist but became an A_2AR antagonist. Interestingly, molecular modeling suggested that structural differences encountered within the third extracellular loop of each receptor could modulate the intrinsic, receptor subtype-dependent, activity. Overall, the development of adenosine receptor ligands with photoswitchable activity expands the pharmacological toolbox in support of research and possibly opens new pharmacotherapeutic opportunities.