Orexin receptors: Targets and applications

Abstract

Over the years, elucidating targets from the neural circuits that can be used to treat disorders pertaining to the nervous system and extending their scope to other systems have always proved interesting to researchers. The role of various peptides and neurotransmitters has been elucidated and is being developed as therapeutic targets. Out of these, orexins are neuropeptides produced in the hypothalamus that stimulate a specific type of G-Protein coupled receptors (GPCR) called orexin receptors and bring about various physiological and pathological roles. Orexin receptors are of interest not only because of their wide applications such as insomnia, obesity, and inflammatory disorders but also because of their contribution to promising aspects of drug discovery such as optogenetics and their tremendous growth from the stage of being orphans to orexins. This review will discuss in detail the structure of orexin receptors, their physiological role, and various applications in disease states adding a note on agonists and antagonists and finally summarizing the recent drug approvals in the field. K E Y W O R D Sagonist, antagonist, orexin system, physiological role | INTRODUCTIONOrexins are neuropeptides involved in regulating many essential physiological functions like sleep-wake transitions, energy metabolism, cognition, and motivation.After 20 years, discovering and delineating the role of orexinergic therapeutics has stopped in research labs but this research has successfully contributed two drugs used in clinic, namely, suvorexant and lemborexant.This review will summarize the critical aspects of the orexinergic system and function and discuss the different applications of orexin receptors as drug targets. It will conclude by discussing the different agonists and antagonists at the receptor and its future prospects.

Physiological Role of Orexinergic System for Health

“…Orexins’ involvement in addiction might be related to their ability to stimulate synaptic function in the main reward areas of the brain. The projections of the orexin system to the NAC, VTA, LC, and DRN represent interactions that well-localize the orexin system as a mediator of the effects of drugs and so forth [ 32 , 43 , 162 , 163 ]. Orexinergic projections to the LC and VTA create a stronger association between arousal and reward-seeking [ 31 ].…”

“…In addicted states, when environmental stimuli related to drug availability are present, the orexin system discharges, stimulating all the neuronal circuitries to activate appropriate behaviors to obtain the drug and then regulating the motivated drug-seeking behaviors that characterize addiction [ 10 ]. Drug-seeking behaviors are increased after orexin stimulation, while OX 1 R antagonists decrease drug-seeking behavior and relapse in model animals [ 163 ]. Specifically, selective OX 1 R antagonists (SORA-1s) reduce various drug-seeking behaviors, mainly those due to drug stimuli, including relapse, without sedative effects [ 10 , 166 ].…”

Orexin Receptor Agonists as Possible Treatment for Narcolepsy and Idiopathic Hypersomnia

“…The biological data obtained from testing the above represented examples are shown in the following table. …”

Novel Macrocyclic Urea Orexin Receptor Agonists for Treating Sleep Disorders

“…The table below shows representative compounds tested for human orexin-2 receptor agonists activity and the biological data obtained from testing the representative examples. …”