Non-peptide orexin 2 receptor modulators as promising way to treatment of narcolepsy/insomnia

Abstract

Narcolepsy is a chronical neurological disorder of alertness characterized by a decrease of ability to manage a sleep-wake cycles which is demonstrated as abnormal daytime sleeping periods, hypersomnia, interrupted nocturnal sleep, cataplexy and rapid eye movement(1). Contrastly, insomnia is sleep disorder characterized by difficulty initiating or maintaining sleep(2). Currently, patients with narcolepsy are treated symptomatically with amphetamine-like stimulants and antidepressants, but it was shown a higher risk of potential addiction(3). Treatment of insomnia involves benzodiazepine-receptor agonist drugs which safety and efficacy is also limited(4). An alternative to treatment of narcolepsy and insomnia would be a direct orexigenic system-targeted therapy(5,6,7). Orexin A and orexinB are neuropeptides produced by hypothalamic neurons and belong to ligands for orphan G-protein coupled receptors, OX1-R and OX2-R(8,9). Generally, the primary role of orexines is to act as excitatory neurotransmitters and regulators of the sleep process(10,11). Accordingly, the discovery of orexin receptors, modulators and their casual implication in narcolepsy/insomnia is the most important advance in sleep-research. The presented work is focused on the evaluation of intrinsic activity of compounds (1-7) to modulate OX2-R in comparison to standard agonist orexin A. Initially, our attempts sought to identify a novel receptor agonist. However, none of ligands showed any significant agonistic effect. In addition, ligands 1, 5 and 6 were able significantly and dose-dependently reduce the signal of orexin A–evoked response, which still offers some promise mainly for the treatment of insomnia. As the most potent antagonist can be highlighted 6. We have also predicted their blood-brain barrier permeability and cytotoxicity.