Target Background

The orexin receptor 1 (OX1, HCRTR1) is a class A G-protein-coupled receptor (GPCR) that mediates the actions of the neuropeptides orexin-A and orexin-B. OX1 is predominantly expressed in the brain, with high density in regions such as the locus coeruleus, ventral tegmental area, and hippocampus, while also showing peripheral expression in the adrenal gland, kidney, and gastrointestinal tract. Its expression profile underscores its essential role in regulating arousal, wakefulness, motivation, and autonomic functions.

Upon binding to orexin-A—its primary ligand—OX1 primarily couples to Gq proteins, leading to phospholipase C activation and increased intracellular calcium levels. This signaling cascade influences neuronal excitability, neurotransmitter release, and synaptic plasticity. In the brain, OX1 activation promotes wakefulness and stabilizes arousal states, while also modulating reward processing, feeding behavior, and emotional responses. Outside the central nervous system, OX1 has been implicated in regulating hormone secretion, gut motility, and energy metabolism.

Pharmacologically, OX1 has emerged as a promising target for sleep-wake disorders and addictive behaviors. OX1 receptor antagonists have been developed to treat insomnia, with selective and dual OX1/OX2 antagonists showing efficacy in promoting sleep onset and maintenance. More recently, OX1 blockade has been explored for substance use disorders and binge eating due to its role in reward and motivation pathways. In parallel, OX1 agonists are under investigation for narcolepsy and other conditions of pathological hypoarousal, offering potential therapeutic avenues to enhance alertness and cognitive performance. With its critical role in maintaining wakefulness and modulating motivated behaviors, OX1 continues to be a key focus of neuropharmacology and the development of novel CNS therapeutics.