Optical control of H₁ receptor signaling with a BODIPY-photocaged antihistamine

Photopharmacology strives for light-dependent regulation of the activity of drug molecules, as a mean for precise control of drug targets on demand and the promise of reduced systemic side effects. Photocaging makes use of photoremovable protecting groups (PPGs), which can be introduced at key positions to inactivate drug ligands. Photocaged ligands can release active drug molecules following light-mediated uncaging with spatiotemporal precision. Here, a boron-dipyrromethene (BODIPY)-based PPG is used to inactivate desloratadine, which is a clinically used histamine H₁ receptor (H₁R) antagonist for the treatment of allergic disorders. The photocaged desloratadine analogue 1 (VUF25549) displays more than 290-fold lower H₁R affinity compared to desloratadine. Irradiation of 1 with 560 nm light results in photo-uncaging and the release of the parent drug desloratadine, resulting in optical modulation of histamine-induced H₁R signaling. The presented BODIPY-based photocaging of desloratadine offers a powerful new tool for the precise optical control of H₁R function.