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Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand
Bahamonde, María Isabel (Institut de Bioenginyeria de Catalunya)
Taura, Jaume (Universitat de Barcelona. Departament Patologia i Terapèutica Experimental)
Paoletta, Silvia (National Institutes of Health)
Gakh, Anadrei A. (National Institutes of Health)
Chakraborty, Saibal (National Institutes of Health)
Hernando Campos, Jordi (Universitat Autònoma de Barcelona. Departament de Química)
Fernández Dueñas, Víctor (Universitat de Barcelona. Departament Patologia i Terapèutica Experimental)
Jacobson, Kenneth A. (National Institutes of Health)
Gorostiza, Pau (Institut de Bioenginyeria de Catalunya)
Ciruela, Francisco (Universitat de Barcelona. Departament Patologia i Terapèutica Experimental)

Date: 2014
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 substituent, which in the dark (relaxed isomer) behaved as a full adenosine A receptor (AR) and partial adenosine A receptor (AR) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full AR agonist but became an AR 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.
Note: This is an open access article published under an ACS AuthorChoice License. See Standard ACS AuthorChoice/Editors' Choice Usage Agreement - https://pubs.acs.org/page/policy/authorchoice_termsofuse.html
Note: Número d'acord de subvenció MINECO/SAF2011-24779
Note: Número d'acord de subvenció MINECO/CTQ2012-30853
Note: Número d'acord de subvenció MINECO/PCIN-2013-019-C03-03
Note: Número d'acord de subvenció MINECO/CSD2008-00005
Note: Número d'acord de subvenció AGAUR/2014/SGR-1054
Note: Número d'acord de subvenció AGAUR/2014/SGR-1251
Note: Número d'acord de subvenció EC/FP7/270483
Note: Número d'acord de subvenció EC/FP7/210355
Note: Número d'acord de subvenció EC/FP7/335011
Rights: Tots els drets reservats.
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: Adenosine A2 Receptor Agonists ; Adenosine A3 Receptor Agonists ; HEK293 Cells ; Humans ; Isomerism ; Ligands ; Molecular Docking Simulation ; Photochemical Processes ; Receptor, Adenosine A2A ; Receptor, Adenosine A3
Published in: Bioconjugate chemistry, Vol. 25, Issue 10 (October 2014) , p. 1847-1854, ISSN 1520-4812

DOI: 10.1021/bc5003373
PMID: 25248077


8 p, 1.6 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Experimental sciences > Group in Electrochemistry, Photochemistry and Organic Reactivity (GEFRO)
Articles > Research articles
Articles > Published articles

 Record created 2019-12-10, last modified 2020-11-23



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