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 de Patologia i Terapèutica Experimental)
Paoletta, Silvia (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Gakh, Anadrei A. (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Chakraborty, Saibal (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Hernando Campos, Jordi (Universitat Autònoma de Barcelona. Departament de Química)
Fernández-Dueñas, Víctor (Universitat de Barcelona. Departament de Patologia i Terapèutica Experimental)
Jacobson, Kenneth A. (National Institutes of Health (Bethesda, Estats Units d'Amèrica))
Gorostiza, Pau (Institut de Bioenginyeria de Catalunya)
Ciruela, Francisco (Universitat de Barcelona. Departament de 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.
Grants:	Ministerio de Economía y Competitividad SAF2011-24779 Ministerio de Economía y Competitividad CTQ2012-30853 Ministerio de Economía y Competitividad PCIN-2013-019-C03-03 Ministerio de Economía y Competitividad CSD2008-00005 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1054 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1251 European Commission 270483 European Commission 210355 European Commission 335011
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
Rights:	Tots els drets reservats.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
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

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > Group in Electrochemistry, Photochemistry and Organic Reactivity (GEFRO)
Articles > Research articles
Articles > Published articles