From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX₂R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX₂R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX₂R. We obtained seven new potential OX₂R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX₂R. Out of them, 15 emerged as the most potent modulator of OX₂R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.