Structure-Based Development of a Subtype-Selective Orexin 1 Receptor Antagonist
Structure-based development of a subtype-selective orexin 1 receptor antagonist Jan Hellmanna,1, Matthäus Drabekb,1, Jie Yinc,1, Jakub Gunerab, Theresa Prölla, Frank Krausa, Christopher J. Langmeadd, Harald Hübnera, Dorothee Weikerta, Peter Kolbb,2, Daniel M. Rosenbaumc,2, and Peter Gmeinera,2 aDepartment of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany; bDepartment of Pharmaceutical Chemistry, Philipps-University Marburg, 35032 Marburg, Germany; cDepartment of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute, Durham, NC, and approved June 18, 2020 (received for review February 12, 2020) Orexins are neuropeptides that activate the rhodopsin-like G protein- in clinical development, e.g., seltorexant, which has been devel- coupled receptors OX1R and OX2R. The orexin system plays an im- oped for the treatment of insomnia and major depressive disor- portant role in the regulation of the sleep-wake cycle and the regu- ders and is currently being investigated in phase II clinical trials lation of feeding and emotions. The nonselective orexin receptor (14). The pharmaceutical potential of selective OX1R antagonists antagonist suvorexant has been the first drug on the market target- for treatment of obesity (15), anxiety (16), and drug addiction ing the orexin system and is prescribed for the treatment of insomnia. (17–19) has been shown in several in vivo experiments. Subtype-selective OX1R antagonists are valuable tools to further in- Structure-based drug design enabled the development of new vestigate the functions and physiological role of the OX1R in vivo and probes with improved selectivity (20, 21) and activities (22) due promising lead compounds for the treatment of drug addiction, anx- to the multitude of novel high-resolution structures.
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