Seltorexant is an orally active, high-affinity, and selective OX2R antagonist with a pKi value of 8.1 for rat OX2R [1]. Seltorexant can cross the blood-brain barrier (BBB) and bind to OX2R, which selectively block OX2R to initiate and prolong sleep [2]. Seltorexant has been widely used to shorten the latency of rapid eye movement (REM) sleep in rats and to prolong the duration of REM sleep [3].
In vivo, Seltorexant treatment via a single subcutaneous injection at a dose of 10mg/kg for 30 minutes acutely reduced responding for sucrose under both sleep deprivation and sleep recovery conditions[4]. Intraperitoneal injection of a 10mg/kg/day dose of Seltorexant for 5 days can increase the anxiety-like behavior in male mice[5].
References:
[1] Bonaventure P, Shelton J, Yun S, et al. Characterization of JNJ-42847922, a selective orexin-2 receptor antagonist, as a clinical candidate for the treatment of insomnia[J]. The Journal of Pharmacology and Experimental Therapeutics, 2015, 354(3): 471-482.
[2] Ziemichód W, Kurowska A, Grabowska K, et al. Characteristics of seltorexant—innovative agent targeting orexin system for the treatment of depression and anxiety[J]. Molecules, 2023, 28(8): 3575.
[3] Mesens S, Krystal A D, Melkote R, et al. Efficacy and safety of seltorexant in insomnia disorder: a randomized clinical trial[J]. JAMA psychiatry, 2025, 82(10): 967-976.
[4] Forbes C, Zeak J, Shelton M, et al. Acute Sleep Deprivation in Adolescence Produces Transcriptional Changes in the Orexin System and Regulates Motivation for Reward[J]. Biological Psychiatry Global Open Science, 2026: 100746.
[5] Chen L, Tian R, Wei S, et al. Activation of orexin receptor 2 plays anxiolytic effect in male mice[J]. Brain Research, 2025, 1859: 149646.