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

• Published in: Bioconjugate chemistry Vol. 25; no. 10; pp. 1847 - 1854
• Main Authors: Bahamonde, María Isabel, Taura, Jaume, Paoletta, Silvia, Gakh, Andrei A, Chakraborty, Saibal, Hernando, Jordi, Fernández-Dueñas, Víctor, Jacobson, Kenneth A, Gorostiza, Pau, Ciruela, Francisco
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.10.2014; Amer Chemical Soc
• Subjects: Adenosine; Adenosine A2 Receptor Agonists - chemistry; Adenosine A2 Receptor Agonists - pharmacology; Adenosine A3 Receptor Agonists - chemistry; Adenosine A3 Receptor Agonists - pharmacology; Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Glycoproteins; HEK293 Cells; Humans; Isomerism; Life Sciences & Biomedicine; Ligands; Molecular Docking Simulation; Molecules; Pharmacology; Photochemical Processes; Physical Sciences; Receptor, Adenosine A2A - chemistry; Receptor, Adenosine A2A - metabolism; Receptor, Adenosine A3 - chemistry; Receptor, Adenosine A3 - metabolism; Science & Technology; T cell receptors; ACTIVATION; RAT; A(2A); CIS-TRANS ISOMERIZATION; DOCKING; AZOBENZENE; CHANNELS; REMOTE; AGONIST
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc5003373

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 A2A receptor (A2AR) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full A3R agonist but became an A2AR 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.