orexin receptor antagonists as therapeutic agents for insomnia

In the late 1990s, the orexin signaling system (also known as the hypocretin system) was discovered and its role in sleep and wake characterized. The orexin neuropeptide signaling system plays a role in wakefulness. doi: 10.1021/acs.jmedchem.5b00832 . Orexin receptor antagonists as therapeutic agents for insomnia. Orexin receptor antagonists as therapeutic agents for insomnia . (2016) 59:504–30. making them less attractive as maintenance therapy. Dual orexin receptor antagonists, also referred to orexin receptor antagonists, are a new class of medication purposefully designed for the treatment of insomnia, 12,16 with suvorexant being the first available treatment in Australia 16 and the US 12. Dual orexin receptor antagonists (DORAs) are a novel therapeutic class of medications for the treatment of insomnia. During the last decade, several groups within the pharmaceutical industry have developed orexin receptor antagonists in order to identify the physiological role of orexin receptors and explore the potential of orexin receptor antagonists as therapeutic agents for management of insomnia . 9 Equihua AC, De La Herrán-Arita AK, Drucker-Colin R Orexin receptor antagonists as therapeutic agents for insomnia. BibTex; Full citation; Abstract. Dual Orexin Receptor Antagonist (DORA) DORA bind to both orexin 1 and orexin 2 receptors Stahl SM. Rhyne DN, Anderson SL. A dual orexin receptor antagonist, Almorexant (ACT-078573, (2R)-2-{(1S)-6, 7-dimethoxy-1-[2-(4-trifluoromethylphenyl)-ethyl]-3,4-dihydro-1H-isoquinolin-2yl-N-methyl-2-phenyl-acetamide), is available from Actelion Pharmaceuticals Ltd. as an oral agent effective in rat and man (Brisbare-Roch et al., 2007).Oral treatment with Almorexant decreased alertness and increased both REM and NREM sleep … The newer drug Belsomra is technically classified as a DORA (dual orexin receptor antagonist) via its selective effects on the OX1 receptor and OX2 receptor. In this review, we outline the role of orexin receptor antagonists in disorders of sleep/wake and other potential neuropsychiatric conditions, with a focus on suvorexant, which is currently the only approved agent in this class. Bonaventure P, Shelton J, Yun S, Nepomuceno D, Sutton S, Aluisio L, et al. 9. These medications work by acting as orexin receptor antagonists, meaning that they block the effects of orexins in the body, reduce the drive to stay awake, and facilitate sleep. The Role of Orexin/Hypocretin in the Central Nervous System and Peripheral Tissues, Tomomi Tsunematsu and Akihiro Yamanaka. In other words, these drugs strictly target orexin receptors and don’t act on other neurotransmission. Janto K, Prichard JR, Pusalavidyasagar S. An update on dual orexin receptor antagonists and their potential role in insomnia therapeutics. Almorexant, development of the drug was abandoned in January 2011; Dayvigo(lemborexant), approved by the FDA in December 2019 and released June 1, 2020 by Merck. Effectiveness is not well established in the current literature; however, the literature does suggest efficacy. BMJ; 2005;3317526:1169, 16284208. Within a few years, Eisai initiated a program to look at the neuropeptide orexin as a therapeutic target for sleep and neurological disorders. The mechanism of action of lemborexant in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance is presumed to be through antagonism of orexin receptors. As an organization accredited by the ACCME, Medscape, LLC requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. J Clin Sleep Med. The discovery of hypocretin and deficiency of these peptides in narcolepsy spurred the development of pharmacological agents that antagonize hypocretin receptors for the treatment of sleep disorders such as insomnia. Suvorexant is the first agent to be approved in this new class and gained US Food and Drug Administration (FDA) approval in 2014. •DORAs’ impact on sleep is comparable to sedative/hypnotics, but side effects are better tolerated in healthy geriatric population. Suvorexant has been studied in 36 trials and 2869 subjects (1784 of those in phase III trials). •Dual Orexin Receptor Antagonists (DORAs) offer an entirely distinct pharmacological approach for treating insomnia. Almorexant (ACT-078573) is an orally active dual orexin receptor antagonist that is being developed by Actelion Ltd, in collaboration with GlaxoSmithKline plc, for the treatment of primary insomnia. 124: Distinct effects of IPSU and suvorexant on mouse sleep architecture. 10. Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. J Med Chem. •Orexin over expression increases beta amyloid production, and DORA infusion prevents this. Identification of patients who may benefit from orexin receptor antagonist therapy; Disclosures. Conclusion: Suvorexant is the first dual orexin receptor antagonist approved for the treatment of insomnia. Front Pharmacol; 2013;4:163, 24416019. Examples. Front. 2013;36(2):259–267. 4: 163 10.3389/fphar.2013.00163 [PMC free article] Etori K., Saito Y. C., Tsujino N., Sakurai T. (2014). Some cognitive behavioural therapy for insomnia (CBT-I) ... Dual orexin receptor antagonists. to cognitive-behavioral therapy and pharmacological agents such as non-benzodiazepine receptor agonists. Several orexin receptor antagonists are in development for potential use in sleep disorders. Orexin receptor antagonists as therapeutic agents for insomnia. Almorexant is a first-in-class compound that targets the orexin system, which plays a key role in wake promotion and stabilization, in addition to having other regulatory functions. Sun H, Kennedy WP, Wilbraham D, et al. For example, since the selectivity of SB‐334867 for OX 1 R is only approximately 50‐fold higher than that for OX 2 R (Haynes et al., 2000; Porter et al., 2001), at higher doses, SB‐334867 is likely to block both orexin receptors, complicating interpretation of results in high dose studies. Front. Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to orexin receptors OX1R and OX2R is thought … Targeting the orexin receptor system for treatment of insomnia offers an additional and alternative pharmacological approach to more common gamma aminobutyric acid agonist sedative hypnotic treatment. Dual orexin receptor antagonists (DORAs) are a new type of prescription sleep aid that targets the body’s orexin system. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states.

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