Kinetic Basis for the\nDesign of Azobenzene-Based Photoswitchable\nA<sub>2a</sub> Adenosine Receptor\nLigands

Photoisomerization of ligands is a key process in the\nfield of\nphotopharmacology. Thus, the kinetics and efficiency of this initial\nphotoreaction are of great importance but can be influenced by the\nmolecular environment of the binding pocket and the resulting confinement\nof the reaction pathway. In this study, we investigated the photoisomerization\nof an azobenzene derivative of the anti-Parkinson’s drug istradefylline.\nTo identify the impact of the binding pocket, the ligand was examined\nin solution and bound to its target protein, the A<sub>2a</sub> adenosine\nreceptor (A<sub>2a</sub>R), belonging to the family of G protein-coupled\nreceptors (GPCRs). Although the overall efficiency of isomerization\nis reduced when the ligand is bound, the initial photoreaction experiences\nlittle influence from the binding pocket. However, protein-coupled\nmotion promotes a longer-lived excited-state population and thus leads\nto a reduction in efficiency. The results provide the kinetic basis\nfor a photoswitchable GPCR ligand and demonstrate the influence of\nthe binding pocket on fundamental photochemistry.