Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs

Abstract

The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine.

Practitioner Review: Treatment of chronic insomnia in children and adolescents with neurodevelopmental disabilities

“…selective for OX1 or OX2 receptors) or dual orexin receptor antagonists (i.e. compound with spread binding capacity to OX1 and OX2; Kumar, Chanana, & Choudhary, 2016). It has been hypothesized that antagonizing both orexin receptors would elicit the most powerful sleep-promoting effects (Morairty et al, 2012).…”

Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study

“…[6][7][8][9][10][11] Impairment of driving abilities the day following ; they help promote wakefulness by binding to the G-protein-coupled receptors, OX1R and OX2R. 9,16 The dual orexin receptor antagonist (DORA) suvorexant (approved in the United States and Japan 17 ) has been shown to treat insomnia disorder and is thought to block the wakefulness that is interfering with sleep. 16 However, higher doses have been associated with residual daytime sleepiness, which is a safety concern.…”

“…9,16 The dual orexin receptor antagonist (DORA) suvorexant (approved in the United States and Japan 17 ) has been shown to treat insomnia disorder and is thought to block the wakefulness that is interfering with sleep. 16 However, higher doses have been associated with residual daytime sleepiness, which is a safety concern. 18 Lemborexant (E2006) is an orally active investigational DORA in clinical development.…”

Oxadiazole Derivatives as Dual Orexin Receptor Antagonists: Synthesis, Structure–Activity Relationships, and Sleep‐Promoting Properties in Rats

“…The first proof of concept for this novel mechanism waso btained with almorexant in 2007, [4] almostadecadea fter the independentd iscoveryo fo rexin neuropeptides (orexin Aa nd orexin B) by two research groups. [18][19][20][21] Whether blockingO X 2 Ra lonei ss ufficient for promoting sleepi n humans was under debate [22][23][24][25][26] until recently when Merck published their results of MK-1064, aS O 2 RA promoting sleep in mouse, dog and human in as imilarm anner to DORAs. Orexin Ab inds to the G-protein-coupled receptors OX 1 Ra nd OX 2 R, whereas orexin Bb inds mainlyt oO X 2 R. Intense research [7][8][9][10][11] resulted in the discovery of DORAs, selective orexin 1r eceptor antagonists (SO 1 RAs) and selectiveo rexin 2 receptor antagonists (SO 2 RAs).…”

“…[12,13] Currently,s everal additional DORAs (e.g.,l emborexant from Eisai, [14] ac ompound from Idorsia [15] )a nd SO 2 RA (MIN-202) [16,17] are being evaluated in clinicals tudies for the treatment of insomnia. [18][19][20][21] Whether blockingO X 2 Ra lonei ss ufficient for promoting sleepi n humans was under debate [22][23][24][25][26] until recently when Merck published their results of MK-1064, aS O 2 RA promoting sleep in mouse, dog and human in as imilarm anner to DORAs. [27] SO 1 RAs are investigated mainly for the treatment of addiction, stress, anxiety, and panic disorders.…”