Optical Control of Adenosine A_2A Receptor Using Istradefylline Photosensitivity

In recent years, there has been growing interest in the potential therapeutic use of inhibitors of adenosine A(2A) receptors (A(2A)R) for the treatment of neurodegenerative diseases and cancer. Nevertheless, the widespread expression of A(2A)R throughout the body emphasizes the importance of temporally and spatially selective ligands. Photopharmacology is an emerging strategy that utilizes photosensitive ligands to attain high spatiotemporal precision and regulate the function of biomolecules using light. In this study, we combined photochemistry and cellular and in vivo photopharmacology to investigate the light sensitivity of the FDA-approved antagonist istradefylline and its potential use as an A(2A)R photopharmacological tool. Our findings reveal that istradefylline exhibits rapid trans-to-cis isomerization under near-UV light, and prolonged exposure results in the formation of photocycloaddition products. We demonstrate that exposure to UV light triggers a time-dependent decrease in the antagonistic activity of istradefylline in A(2A)R-expressing cells and enables real-time optical control of A(2A)R signaling in living cells and zebrafish. Together, these data demonstrate that istradefylline is a photoinactivatable A(2A)R antagonist and that this property can be utilized to perform photopharmacological experiments in living cells and animals.