title: Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.
abstract: 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 N(6) 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.
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC) , 08028 Barcelona, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Bahamonde
authors.forename: Jaume
authors.initials: J
authors.lastname: Taura
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Gakh
authors.forename: Saibal
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Jordi
authors.initials: J
authors.lastname: Hernando
authors.forename: Víctor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Pau
authors.initials: P
authors.lastname: Gorostiza
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D058909:Adenosine A3 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D008024:Ligands; D062105:Molecular Docking Simulation; D055668:Photochemical Processes; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D008024:Ligands; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3