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.

• Keywords
• narcolepsy, orexin A, orexin receptor modulators, structure-based virtual screening, suvorexant,
• MeSH
• Orexin Receptor Antagonists chemistry   pharmacology   MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Inhibitory Concentration 50 MeSH
• Quantitative Structure-Activity Relationship MeSH
• Ligands MeSH
• Molecular Conformation MeSH
• Models, Molecular * MeSH
• Molecular Structure MeSH
• Orexin Receptors chemistry   MeSH
• Orexins chemistry   pharmacology   MeSH
• Computer Simulation * MeSH
• Drug Design * MeSH
• Protein Binding MeSH
• Binding Sites MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Orexin Receptor Antagonists MeSH
• Ligands MeSH
• Orexin Receptors MeSH
• Orexins MeSH