Design and synthesis of photoswitchable desloratadine ligands for histamine H ₁ receptor photopharmacology

Despite the pharmacological relevance of the histamine H₁ receptor (H₁R), 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 H₁R ligand by performing an 'azoscan' on the H₁R 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 H₁R. Additionally, we functionalized the piperidine ring of desloratadine with azobenzene moieties. These two strategies resulted in a total of nine photoswitchable compounds, displaying efficient <i>trans</i> to <i>cis</i> isomerization (PSS _<i>cis</i> > 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 (<i>K</i> _i <i>trans</i> = 2 nM) and a 3.2-fold light-induced affinity shift. Computational docking studies provide a rationale, with the binding pose of the <i>trans</i> and <i>cis</i> isomer in the H₁R binding pocket potentially being inverted. While the development of effective photoswitchable ligands for H₁R remains challenging, this study provides promising opportunities for future optimization to achieve optical control of this GPCR.