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

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

  • Bioorg Chem. 2020 Oct;103:104179. doi: 10.1016/j.bioorg.2020.104179.
Eva Mezeiova 1 Jana Janockova 1 Jan Konecny 1 Tereza Kobrlova 1 Marketa Benkova 1 Rafael Dolezal 1 Lukas Prchal 1 Jana Karasova-Zdarova 1 Ondrej Soukup 2 Jan Korabecny 3
Affiliations

Affiliations

  • 1 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
  • 2 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: ondrej.soukup@fnhk.cz.
  • 3 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: jan.korabecny@fnhk.cz.
Abstract

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.

Keywords

Insomnia; Orexin 2 receptor antagonist; Sleep disorder; Suvorexant; YNT-185.

Figures
Products