Photoisomerization of ligands is a key process in the field of photopharmacology. Thus, the kinetics and efficiency of this initial photoreaction are of great importance but can be influenced by the molecular environment of the binding pocket and the resulting confinement of the reaction pathway. In this study, we investigated the photoisomerization of an azobenzene derivative of the anti-Parkinson’s drug istradefylline. To identify the impact of the binding pocket, the ligand was examined in solution and bound to its target protein, the A_2a adenosine receptor (A_2aR), belonging to the family of G protein-coupled receptors (GPCRs). Although the overall efficiency of isomerization is reduced when the ligand is bound, the initial photoreaction experiences little influence from the binding pocket. However, protein-coupled motion promotes a longer-lived excited-state population and thus leads to a reduction in efficiency. The results provide the kinetic basis for a photoswitchable GPCR ligand and demonstrate the influence of the binding pocket on fundamental photochemistry.