LAUSR

&NA; G 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 A2A receptor (A2AR) antagonist to photocontrol movement disorders. We synthesized MRS7145 by blocking with coumarin the 5‐amino position of the selective A2AR antagonist SCH442416, which could be photoreleased upon violet light illumination (405 nm). First, the light‐dependent pharmacological profile of MRS7145 was determined in A2AR‐expressing cells. Upon photoactivation, MRS7145 precluded A2AR ligand binding and agonist‐induced cAMP accumulation. Next, the ability of MRS7145 to block A2AR in a light‐dependent manner was assessed in vivo. To this end, A2AR 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 A2AR antagonist with potential utility to manage movement disorders, including PD. Graphical abstract Figure. No Caption available.