Abstract
Despite the pharmacological relevance of the histamine H(1) receptor (H(1)R), 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 H(1)R ligand by performing an 'azoscan' on the H(1)R 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 H(1)R. Additionally, we functionalized the piperidine ring of desloratadine with azobenzene moieties. These two strategies resulted in a total of nine photoswitchable compounds, displaying efficient trans to cis isomerization (PSS (cis) > 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 (K (i) trans = 2 nM) and a 3.2-fold light-induced affinity shift. Computational docking studies provide a rationale, with the binding pose of the trans and cis isomer in the H(1)R binding pocket potentially being inverted. While the development of effective photoswitchable ligands for H(1)R remains challenging, this study provides promising opportunities for future optimization to achieve optical control of this GPCR.