Orexin receptor type 2 (OX2R) (OX2R)

The Orexin receptor type 2 (OX2R) is a G protein-coupled receptor (GPCR) that plays a fundamental role in the regulation of the sleep-wake cycle and energy homeostasis (UniProt P48346). It is one of two receptors activated by the neuropeptides orexin-A and orexin-B, which are secreted by neurons in the lateral hypothalamus (IUPHAR). While OX1R binds orexin-A with higher affinity, OX2R binds both orexin-A and orexin-B with similar high affinity and is considered the primary mediator of the wake-promoting effects of the orexin system (PubMed PMID: 21871011). Genetic or autoimmune-mediated loss of orexin-producing neurons or dysfunction of the OX2R pathway leads to narcolepsy, a disorder characterized by excessive daytime sleepiness and cataplexy (PubMed PMID: 10433868). Consequently, OX2R has become a significant therapeutic target in sleep medicine. Dual orexin receptor antagonists (DORAs), such as suvorexant and daridorexant, are FDA-approved for the treatment of insomnia, working by blocking the arousal-promoting signals of orexins (FDA Label). Additionally, selective OX2R agonists are currently in clinical development as potential disease-modifying treatments for narcolepsy type 1 and type 2 (PubMed PMID: 34144040). These agonists aim to restore the missing orexin signaling to stabilize wakefulness and prevent cataplexy. Beyond sleep, OX2R is also being investigated for its role in mood disorders and substance use (PubMed PMID: 26072068).

Other names

Hypocretin receptor type 2HCRTR2OX2-ROrexin-2 receptor

Drugs targeting the Orexin receptor type 2 function as either antagonists or agonists. Dual orexin receptor antagonists (DORAs) and selective OX2R antagonists (SORAs) block the binding of wake-promoting orexin neuropeptides, thereby facilitating sleep and treating insomnia (PubMed PMID: 28338585). Conversely, selective OX2R agonists are designed to mimic the activity of endogenous orexins at the OX2R to promote wakefulness and stability in patients with narcolepsy (PubMed PMID: 34144040).