Anales RANF

CPL-05 Lecture in Honour Prof Bertil Fredholm LIGHTING UP ADENOSINE RECEPTORS Francisco Ciruela Alférez. Universidad de Barcelona, Spain. Adenosine, a ubiquitous extracellular signaling molecule, acts through cell surface G protein-coupled receptors. These receptors control many physiological functions, thus becoming promising therapeutic targets in a wide range of pathological conditions. Yet, the ubiquity of adenosine receptors and the eventual lack of selectivity of adenosine-based drugs often reduced the therapeutic expectations. Photopharmacology is a novel approach based on the use of photosensitive drugs allowing spatiotemporal control of receptor function in a light-dependent manner, thus circumventing some of the classical pharmacology limitations. Accordingly, we developed light-sensitive drugs to photocontrol adenosine receptor’s function both in vitro and in vivo . To this end, two types of adenosine-based photosensitive drugs were developed: i) Photswitchable; and ii) Photocaged. MRS5543 is a photoisomerizable nucleoside derivative containing an aryl diazo linkage on the N(6) substituent. Interestingly, while in dark conditions ( i.e. relaxed isomer) it behaves as a full adenosine A 3 receptor (A 3 R) and partial adenosine A 2A receptor (A 2A R) agonist, but upon photoisomerization with blue light it turns into an A 2A R antagonist 1 . Thus, MRS5543 is a photoswitchable purinergic drug that allow a light-dependent control of A 2A R intrinsic activity. Conversely, MRS7145 is a photocaged A 2A R antagonist which binds and blocks A 2A R in a light-dependent manner both in cells and in vivo . Thus, precise fibre optic brain irradiation allows MRS7145 uncaging and striatal A 2A R blockade, thus fine-tuning A 2A R-dependent spontaneous locomotor activity and reversing pharmacologically-induced Parkinsonian-like behaviour 2 . Overall, the design and synthesis of light-operated adenosine receptor ligands opens new opportunities to widen the phototherapeutic window of adenosine receptors. References 1 Bahamonde MI, Taura J, Paoletta S, Gakh AA, Chakraborty S, Hernando J et al. Photomodulation of G protein-coupled adenosine receptors by a novel light- switchable ligand. Bioconjugate Chemistry 2014; 25 : 1847–1854. 2 Taura J, Nolen EG, Cabré G, Hernando J, Squarcialupi L, López-Cano M et al. Remote control of movement disorders using a photoactive adenosine A 2A receptor antagonist. Journal of Controlled Release 2018; 283 : 135–142.