Targeting the orexinergic system: Mainly but not only for sleep-wakefulness therapies

Orexin receptors belong to the big family of G protein coupled receptors (GPCRs) that constitute the main targets in the modern pharmacological approaches. Although the orexinergic system is involved in a variety of processes, treating sleep-wakefulness disorders such as narcolepsy and insomnia, remains the main therapeutic implication of targeting orexinergic receptors. After novel advances, such as the description of the binding pockets, and ligand developments, more researchers are focusing on orexin receptors as promising targets. Furthermore, targeting these receptors may provide therapeutic solutions for some health problems, other than sleep-wakefulness disorders including some psychiatric disorders and neurodegenerative diseases. Within this paper, we put a spotlight on the orexins’ physiology, pathophysiology and pharmacology of mainly sleep-wakefulness. We have also reviewed examples about other orexinergic system-related disorders. We further illustrated recent development in orexin receptors’ agonists and antagonists. In addition, we discussed selected progresses in orexinergic receptors’ ligands.