Towards the Next Generation of Photoswitchable Ligands in GPCR Photopharmacology

The ability to control biological processes with high spatial and temporal precision remains a major challenge in modern drug discovery. Light-based approaches have emerged to address this challenge, enabling dynamic control of biological targets while reducing off-target effects. Among these approaches, photopharmacology uses light-responsive ligands the biological activity of which can be reversibly controlled through irradiation with light. Photoswitchable ligands offer the possibility to modulate protein function with high precision, making them attractive compounds for research. Despite substantial advances in the field, many photoswitchable ligands still rely on the azobenzene scaffold, and switching this group from its trans to its cis configuration generally calls for ultraviolet (UV) irradiation. As a result, their applicability in living systems is limited, since UV wavelengths are absorbed before they can reach deeper tissue layers.

G protein-coupled receptors (GPCRs) constitute one of the most important classes of drug targets and have become a major focus of photopharmacological research. Several photoswitchable ligands for histamine receptors have already been developed in the past. Building on this foundation, this thesis explores the design, synthesis, and characterization of next-generation photoswitchable GPCR ligands. Particular emphasis is placed on expanding the photopharmacological toolbox beyond conventional azobenzenes by exploring alternative heteroaryl photoswitches and evaluating how these structural modifications influence both photochemical and pharmacological properties. Together, these studies aim to contribute to the development of more effective and biologically compatible photoswitchable ligands for GPCR photopharmacology. […]