Mezeiova_2020_Bioorg.Chem_103_104179

YNT-185 is the first known small molecule acting as orexin 2 receptor (OX(2)R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX(2)R. 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 OX(2)R. We obtained seven new potential OX(2)R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX(2)R. Out of them, 15 emerged as the most potent modulator of OX(2)R, 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.