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

• Small set of seven compounds was developed building upon YNT-185. • Compounds were tested as orexin receptor type 2 modulators. • Switch from agonist (YNT-185) to antagonist (new compounds) was observed. • Compounds retained low cytotoxicity profile and predicted CNS availability. • Top-ranked compound 15 was submitted to pharmacokinetic study in vivo. 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. [ABSTRACT FROM AUTHOR]