Neuroscience of Orexins, and Design and Synthesis of Orexin 2 Receptor Agonist, YNT-185

Abstract

Orexin-A and orexin-B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors. They play critical roles in the maintenance of wakefulness by regulating function of monoaminergic and cholinergic neurons that are implicated in regulation of wakefulness. Loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, further suggesting the particular importance of orexin in maintenance of the wakefulness state. These findings have encouraged pharmaceutical companies to develop drugs targeting orexin receptors as novel medications of sleep disorders, such as narcolepsy and insomnia. Indeed, one of the antagonists, suvorexant, was released in Japan in 2014 and in US in 2015 for treatment of primary insomnia. We also tried to design and synthesize orexin2 receptor agonists which are expected to be a drug for narcolepsy. We paid attention to the sulfonamide group in hit compounds obtained at University of Texas and tried to extend the structure of the OX2R antagonists to afford the agonists. As a result, the first potent and selective agonist for OX2R, YN-1055 was obtained. The resulting agonist was modified to dissolve in water to yield YNT-185 which showed arousal effect via intracerbroventicular and intraperitoneal injections. Furthermore, YNT-185 attenuated the symptom in narcolepsy model mice.