From Darkness to Precision: Modulation of Histamine Receptor Signaling with Light

Photopharmacology focuses on modulaton of biological targets with light in the presence of photosensitive ligands. An active ligand can be synthetically modified to contain a photosensitive moiety (photocage), thereby hindering ligand activity. With light, the active ligand can be irreversibly uncaged via photocage cleavage, thereby restoring the ligand activity. The second group of ligands, called photoswitchable ligands, contain a photosensitive moiety (e.g. azobenzene), which does not get cleaved from the active ligand, but only changes physicochemical properties and shape upon light illumination. This change can lead to a spatial readjustment of the photoswitchable ligand, which can lead to ligand readjustment in the binding pocket of a biological target. This light-induced change in a photoswichable ligand can further lead to a change in activity of a biological target. Hence, the potential of photopharmacology lies in controllable drug action – using light to guide ligand-target interactions with spatio-temporal precision, potentially lowering side effects in a translational setting.

G protein-coupled receptors (GPCRs) are prominent drug targets, being the largest family of membrane receptors in humans. Most photoswitchable ligands targeting GPCRs are modified mainly with ultraviolet (UV) light. Yet, UV light is known to cause tissue damage and has low tissue penetration. This has prompted the field to search for optimized photo-moieties, i.e. groups that can be modulated by longer and less damaging wavelengths, preferably in the visible spectrum.

The focus of this thesis is the photopharmacology of the histamine H1, H3 and H4 receptors, GPCRs involved in various pathophysiologies from immunomodulation to neurodegeneration. The aim of this thesis has been to synthesize new small molecule phototools to enable optical target modulation with spatio-temporal precision, as well as develop and optimize assays for photopharmacological in vitro characterization of these tool compounds. […]