Structure-Based Development Of A Subtype-Selective Orexin 1 Receptor Antagonist

Orexins are neuropeptides that activate the rhodopsin-like G protein -coupled receptors OX1R and OX2R. The orexin system plays an im-portant role in the regulation of the sleep-wake cycle and the regu-lation of feeding and emotions. The nonselective orexin receptor antagonist suvorexant has been the first drug on the market target-ing the orexin system and is prescribed for the treatment of insomnia. Subtype-selective OX1R antagonists are valuable tools to further in-vestigate the functions and physiological role of the OX1R in vivo and promising lead compounds for the treatment of drug addiction, anx-iety, pain or obesity. Starting from the OX1R and OX2R crystal struc-tures bound to suvorexant, we exploited a single amino acid difference in the orthosteric binding site by using molecular docking and structure-based drug design to optimize ligand interactions with the OX1R while introducing repulsive interactions with the OX2R. A newly established enantiospecific synthesis provided li-gands showing up to 75-fold selectivity for the OX1R over the OX2R subtype. The structure of a new OX1R antagonist with sub-nanomolar affinity (JH112) was determined by crystallography in complex with the OX1R and corresponded closely to the docking -predicted geometry. JH112 exhibits high selectivity over a panel of different GPCRs, is able to cross the blood-brain barrier and acts as slowly diffusing and insurmountable antagonist for Gq protein acti-vation and in particular beta-arrestin-2 recruitment at OX1R. This study demonstrates the potential of structure-based drug design to de-velop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound.