Investigation of new orexin 2 receptor modulators using in silico and in vitro methods

Author
Janockova, Jana
Dolezal, Rafael
Nepovimova, Eugenie
Kobrlova, Tereza
Benkova, Marketa
Kuca, Kamil
Konecny, Jan
Mezeiova, Eva
Melikova, Michaela
Hepnarova, Vendula
Ring, Avi
Soukup, Ondrej
Korabecny, Jan
Date Issued
2018
Keywords
Narkolepsi
Søvn
Oreksin
Permalink
http://hdl.handle.net/123456789/76246
http://hdl.handle.net/20.500.12242/2505
DOI
10.3390/molecules23112926
Collection
Articles
Description
Janockova, Jana; Dolezal, Rafael; Nepovimova, Eugenie; Kobrlova, Tereza; Benkova, Marketa; Kuca, Kamil; Konecny, Jan; Mezeiova, Eva; Melikova, Michaela; Hepnarova, Vendula; Ring, Avi; Soukup, Ondrej; Korabecny, Jan. Investigation of new orexin 2 receptor modulators using in silico and in vitro methods. Molecules 2018 ;Volum 23.(11)
1647801.pdf
Size: 5M
Abstract
The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1–L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 µM, offering some promise mainly for the treatment of insomnia.
View Meta Data