Taura, JaumeNolen, Ernest G.Cabre, GiselaHernando, JordiSquarcialupi, LuciaLópez-Cano, MarcJacobson, Kenneth A.Fernández Dueñas, VíctorCiruela Alférez, Francisco2020-11-242020-11-242018-08-10https://hdl.handle.net/2445/172324G protein-coupled adenosine receptors are promising therapeutic targets for a wide range of neuropathological conditions, including Parkinson's disease (PD). However, the ubiquity of adenosine receptors and the ultimate lack of selectivity of certain adenosine-based drugs have frequently diminished their therapeutic use. Photopharmacology is a novel approach that allows the spatiotemporal control of receptor function, thus circumventing some of these limitations. Here, we aimed to develop a light-sensitive caged adenosine A(2A) receptor (A(2A)R) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5-amino position of the selective A(2A)R antagonist SCH442416, which could be photoreleased upon violet light illumination (405 nm). First, the light-dependent pharmacological profile of MRS7145 was determined in A(2A)R-expressing cells. Upon photoactivation, MRS7145 precluded A(2A)R ligand binding and agonist-induced cAMP accumulation. Next, the ability of MRS7145 to block A(2A)R in a light-dependent manner was assessed in vivo. To this end, A(2A)R antagonist-mediated locomotor activity potentiation was evaluated in brain (striatum) fiber-optic implanted mice. Upon irradiation (405 nm) of the dorsal striatum, MRS7145 induced significant hyperlocomotion and counteracted haloperidol-induced catalepsy and pilocarpine-induced tremor. Finally, its efficacy in reversing motor impairment was evaluated in a PD animal model, namely the hemiparkinsonian 6-hydroxydopamine (6-OHDA)-lesioned mouse. Photo-activated MRS7145 was able to potentiate the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine (L-DOPA). Overall, MRS7145 is a new light-operated A(2A)R antagonist with potential utility to manage movement disorders, including PD.8 p.application/pdfengcc by-nc-nd (c) Elsevier, 2018http://creativecommons.org/licenses/by-nc-nd/3.0/es/Malaltia de ParkinsonAdenosinaParkinson's diseaseAdenosineinfo:eu-repo/semantics/article2020-11-11info:eu-repo/semantics/openAccess29859955