Filorexant is an Orally Active and Selective Antagonist of OX1 and OX2 Receptor

The orexin receptors (hypocretin receptors) are a family of G protein-coupled receptors and consist of orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) subtypes. Orexin receptors play important roles in the regulation of the sleep/wake cycle. In addition, the 2 orexin peptides, orexin-A and orexin-B, bind to both receptors. Specifically, orexin A binding to OX1R and OX2R with similar affinity, and orexin B binding to OX2 with higher affinity. Moreover, both OX1R and OX2R are coupled via Gq/11 to the activation of phospholipase C. And then, OX1R and OX2R can elevation of intracellular Ca2+ levels. Orexin levels exhibit a diurnal pattern, with orexinergic neurons firing actively during wakefulness and becoming virtually silent during the normal sleep period. In recent years, several orexin receptor antagonists are in development for potential use in sleep disorders.

Filorexant (also known as MK-6096) is a potent, orally active, selective, and reversible Orexin 1 (OX1) and OX2 receptor antagonist. In radioligand binding and functional cell based assays, Filorexant shows potent binding and antagonism of both human OX1R and OX2R. However, Filorexant displays less activities against other receptors and enzymes. In addition, Filorexant has the potential for insomnia research. For example, Filorexant reduces locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25-0.5 mg/kg) in a dose-dependent manner. Thus, Filorexant has desirable pharmacological properties, and can enable significant reductions in wakefulness and corresponding increases in NREM (non-rapid eye movement sleep) and REM (rapid eye movement sleep) sleep across species.

To sum up, Filorexant is an orally active, selective, and reversible OX1 and OX2 receptor antagonist, and has the potential for insomnia research.


[1] Christopher J Winrow, et al. Neuropharmacology. 2012 Feb;62(2):978-87.