OX₂ Receptor

OX₂ receptor (OX₂R/HCRTR2) is a class A G protein-coupled receptor activated by orexin-A and orexin-B, two hypothalamic neuropeptides derived from prepro-orexin^[1]. Mechanistically, this orexin receptor system links hypothalamic neuropeptide signaling to feeding behavior, arousal biology, and sleep-wake regulation^[1][2]. In disease models, loss of orexin signaling produces narcolepsy-like phenotypes, and orexin knockout mice show disrupted sleep regulation^[2]. Receptor-specific models further show that OX₂R deficiency and orexin- states produce distinct narcolepsy syndromes, supporting OX₂R as a central node for non-REM and REM sleep regulatory processes^[3]. Compared with OX₁R, OX₂R remains especially important because orexin-B displays stronger functional preference for OX₂R, while both receptor subtypes mediate overlapping but separable orexin biology^[1][3]. Structural studies of human OX₂R bound to suvorexant define an orthosteric antagonist-binding pocket that supports rational ligand design for sleep and wake research^[4]. For experimental applications, the nonpeptide OX₂R-selective agonist YNT-185 ameliorated narcolepsy-cataplexy symptoms in mouse models, providing pharmacological proof of concept for OX₂R activation^[5]. Clinically, an oral OX₂R-selective agonist improved sleepiness and cataplexy measures in narcolepsy type 1 but was associated with liver safety limitations^[6].