Probing chemical space and conformational changes for subtype-selective orexin receptor antagonists.

The orexin system, acting through OX1R and OX2R receptors, plays a key role in the regulation of sleep, motivation, and reward-related processes, making it a promising therapeutic target. While dual OXR antagonists are approved for the treatment of insomnia, the selective modulation of individual receptor subtypes remains poorly understood. In particular, the role of OX1R in neuropsychiatric disorders is still largely unexplored. In this study, we combined fragment-based and structure-based drug design approaches to investigate the structural determinants of underlying subtype selectivity in orexin receptor ligands. Through the exploration of novel aryl(amine) moieties, the modulation of aza-cyclic linker geometry, and the optimization of aryl amide cores, we identified key conformational features and substitution patterns governing receptor selectivity. This approach led to the discovery of antagonists with >10-30-fold selectivity for OX1R, and/or >30-100-fold selectivity for OX2R, as demonstrated by radioligand binding and Gq-mediated functional assays (IP1 and Ca2+ signaling). Given the close interplay among the orexin, dopamine and opioid systems in reward and motivation pathways, herein we further highlight the compatibility of dopaminergic and opioid-related scaffolds in expanding the chemical space for OXR ligand design.