1. From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia
- Author
-
Tereza Kobrlova, Jana Karasova-Zdarova, Jana Janockova, Ondrej Soukup, Jan Korabecny, Marketa Benkova, Eva Mezeiova, Rafael Dolezal, Lukas Prchal, and Jan Konecny
- Subjects
Agonist ,medicine.drug_class ,In silico ,Pharmacology ,01 natural sciences ,Biochemistry ,Orexin Receptors ,Sleep Initiation and Maintenance Disorders ,Drug Discovery ,medicine ,Humans ,Mode of action ,Molecular Biology ,Aniline Compounds ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Suvorexant ,Antagonist ,Small molecule ,Orexin receptor ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Benzamides - 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.
- Published
- 2020
- Full Text
- View/download PDF