Despite the pharmacological relevance of the histamine H receptor (HR), the second most therapeutically targeted G protein-coupled receptor (GPCR), an effective photoswitchable ligand to optically control this receptor remains elusive. In this work, we aimed to identify a suitable photoswitchable HR ligand by performing an 'azoscan' on the HR antagonist desloratadine. Taking advantage of the synthetic toolbox available for the desloratadine scaffold, aniline groups were regioselectively installed on the aromatic positions of this scaffold to enable the synthesis of azobenzene analogs targeting the orthosteric binding pocket of HR. Additionally, we functionalized the piperidine ring of desloratadine with azobenzene moieties. These two strategies resulted in a total of nine photoswitchable compounds, displaying efficient to isomerization (PSS > 87%) and a broad range of thermal relaxation half-lives. Pharmacological evaluation revealed the 2-position (10a) to be most suitable for accommodation of a photoswitchable group, as it exhibits the most balanced profile in absolute affinity ( = 2 nM) and a 3.2-fold light-induced affinity shift. Computational docking studies provide a rationale, with the binding pose of the and isomer in the HR binding pocket potentially being inverted. While the development of effective photoswitchable ligands for HR remains challenging, this study provides promising opportunities for future optimization to achieve optical control of this GPCR.