Orexin receptors: a journey through their discovery to the development of suvorexant, the new sleeping pill

Anandabaskar, Nishanthi; Vimal, Mourouguessine; Selvarajan, Sandhiya; Dkhar, Steven Aibor

doi:10.18203/2319-2003.ijbcp20161493

Cited by 2 publications

(5 citation statements)

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“…OX antagonists can block both OX1R and OX2R, so called DORAs, or can block one single receptor subtype, hence called single orexin receptor antagonist (SORA). Considering the common mechanism of action of conventional hypnotics, reinforcing gamma-aminobutyric acid (GABA) neurotransmission, precipitating daytime sedation, and motor instability and incoordination, added to their abuse because of tolerance and dependence [ 269 ], OX antagonists seem privileged, to some extent. Most of the research work converged on DORAs, of which some members received the FDA-approval, promoted as sleep aids, by their novel mechanism involving the reversible binding to OXRs, supporting the induction and maintenance of sleep [ 270 , 271 ]; however, they can lead to daytime sleepiness, suicidal ideation, and respiratory depression [ 272 ].…”

Section: Reviewmentioning

confidence: 99%

A Bitter Experience That Enlightens the Future: COVID-19 Neurological Affection and Perspectives on the Orexigenic System

Abdelmissih¹

2022

Cureus

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The history of coronaviruses revealed that these viruses caused multiple outbreaks in the past, including a previous severe acute respiratory syndrome (SARS) outbreak in 2003. In 2019, a novel SARS virus, SARS-CoV-2, started a drastic pandemic that, up till now, keeps peaking in successive waves owing to the mutational ability of the virus versus the short-term immunity against it. Although the angiotensinconverting enzyme 2 (ACE2) is the gate through which the virus gets access to human cells, yet ACE2 is deemed protective in lung injury yielding vasodilator, anti-fibrotic, and anti-inflammatory peptides. The viral-provoked ACE2 downregulation aggravated a subsequent potentially lethal cytokine storm. Both the tumor necrosis factor-alpha (TNF-α) receptor (TNFR), activated by the proinflammatory cytokine, TNF-α, released during coronavirus disease 2019 (COVID-19), and ACE2 are cleaved by tumor necrosis convertase enzyme (TACE) to render respective soluble decoy mediators. Several risk factors were linked to COVID-19 morbidity and neurological affection, including obesity and diabetes mellitus (DM), attributed to ACE2 overexpression in obesity, a low-grade inflammatory state with both obesity and DM, and defective lung reparative machinery, added to low tissue-to-lung ACE2 expression in DM. The ACE2 shedding by SARS-CoV-2 upon its entry into the brain, together with the inflammatory cytokines invading the brain, predispose to such neurological affection. However, ACE2 was not sufficient to justify the occurrence of neurological disorders with COVID-19, owing to its lower brain expression, relative to other tissues. Other mediators should have contributed to such neurological disorders, of which, orexins (OXs) are discussed, owing to multiple functional similarities to ACE2. Eventually, this review highlights such similarities selected according to their possible relevance to COVID-19 symptomatology and pathology. Both ACE2 and OXs confer anti-inflammatory benefits, reduce cerebral endothelial dysfunction, promote neuronal survival and neurogenesis, and add to their therapeutic potentiality in sepsis. Both ACE2 and OXs assist in moderating the stress responses and the stress-activated hypothalamic-pituitary-adrenal axis. Both ACE2 and OXs are affected by obesity and DM. The loss of ACE2 and OXs signaling was suggested in neuro-inflammatory and neurodegenerative diseases. Of interest is the abundance of OXs in the dissemination routes to the brain, namely, the peripheral olfactory and the enteric systems. The presumptive role of OXs as analgesics and antipyretics might add to their favorable profile. Advantageously, the availability of OXs agonists and antagonists makes it applicable to corroborate or abrogate the future utility of targeting the orexigenic system in terms of COVID-19 neurological affection. Elaborative work, exploring in vitro and in vivo models, is recommended to identify or deny such perspective involvement.

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Section: Reviewmentioning

confidence: 99%

A Bitter Experience That Enlightens the Future: COVID-19 Neurological Affection and Perspectives on the Orexigenic System

Abdelmissih¹

2022

Cureus

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“…The main challenge with the drugs blocking orexin receptors lies with proving the efficacy as well as safety in the real-world population and identifying the group of insomnia patients who will benefit the most out of it. More studies are required to identify the exact neuronal site involved rather than a generalized hypothesis [1,6]. Similarly, evaluation of OXR antagonists is needed in a specific group of insomnia cases like comorbidities, liver, renal impairment, and other coexisting psychiatric disorders.…”

Section: Challenges and Future Aheadmentioning

confidence: 99%

“…Other groups of drugs like antidepressants also have reported similar side effects apart from anticholinergic side effects. According to the study by Wilsm et al (2000), an ideal drug for insomnia should have the following attributes like rapid absorption and should cause rapid induction of sleep, maintain normal sleep pattern, novel mechanism of action and no effects on gait balance or harmful interaction, no memory disturbance, and no abuse potential [6][7][8].…”

Section: Sleep-related Disordersmentioning

confidence: 99%

“…Insomnia is characterized by difficulty in initiation and maintenance of sleep and impaired daytime functioning. Current therapy for insomnia includes both pharmacological and nonpharmacological interventions, but limitations arise for the pharmacological treatments owing to their adverse effects [6]. Orexins are found to promote arousal by regulating sleep alertness pathways, and hence, orexin antagonists are being considered as a promising choice because of their favorable adverse effect profile [7].…”

Section: Sleep-related Disordersmentioning

confidence: 99%

“…Some of the SORA targeting OX1R are SB-334887, SB-408124, SB-674042, EMPA, and MK-1064 which is currently in clinical trials target OX2R [6].…”

Section: Single Orexin Receptor Antagonistsmentioning

confidence: 99%

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Orexin receptors: Targets and applications

Subramanian

Ravichandran

2021

Fundamemntal Clinical Pharma

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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.

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Orexin receptors: a journey through their discovery to the development of suvorexant, the new sleeping pill

Cited by 2 publications

References 20 publications

A Bitter Experience That Enlightens the Future: COVID-19 Neurological Affection and Perspectives on the Orexigenic System

A Bitter Experience That Enlightens the Future: COVID-19 Neurological Affection and Perspectives on the Orexigenic System

Orexin receptors: Targets and applications

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