Journal
BIOCONJUGATE CHEMISTRY
Volume 25, Issue 10, Pages 1847-1854Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bc5003373
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Funding
- Ministerio de Economia y Competitividad (MINECO) [SAF2011-24779, CTQ2012-30853, PCIN-2013-019-C03-03, Consolider-Ingenio CSD2008-00005]
- Catalan Institution for Research and Advanced Studies (ICREA)
- U.S. Department of Energy in collaboration with the National Cancer Institute
- Beatriu de Pinos (Generalitat de Catalunya)
- Marie Curie (European Union)
- European Union [270483, 210355, 335011]
- RecerCaixa foundation [2010ACUP00378]
- Marato de TV3 foundation [111531]
- ICREA Funding Source: Custom
- European Research Council (ERC) [335011, 210355] Funding Source: European Research Council (ERC)
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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 A(3) receptor (A(3)R) and partial adenosine A(2A) receptor (A(2A)R) agonist. Conversely, upon photoisomerization with blue light (460 nm), it remained a full A3R agonist but became an A(2A)R 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.
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