Discovery of a New Class of Orexin 2 Receptor Agonists as a Potential Treatment for Narcolepsy

Abstract

The orexinergic system, projecting from the lateral hypothalamus, operates through two receptors, orexin receptor type-1 (OX₁) and orexin receptor type-2 (OX₂), stabilizing wakefulness, mainly via OX₂. Narcolepsy Type 1 (NT1) is characterized by excessive sleepiness and cataplexy, and is linked to a loss of orexin-producing neurons. Current therapies manage the symptoms but do not address the underlying cause of the disease. For example, psychostimulants (e.g., modafinil) reduce excessive daytime sleepiness (EDS) and sodium oxybate (gammaaminobutyric acid receptor agonist) reduces both EDS and cataplexy. Despite decades of research, no small-molecule OX₂ agonist has reached the market. This study presents the discovery of two new brain-penetrant, orally bioavailable OX₂ agonists with a phenylglycine-like scaffold. These compounds stabilized wakefulness and reduced cataplexy in a mouse model of NT1. In healthy dogs, they increased time in wakefulness. These results highlight their potential as treatment for narcolepsy and other types of hypersomnolence.