Suvorexant: The first orexin receptor antagonist to treat insomnia

Abstract

Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.

Advances in the management of chronic insomnia

“…120 In addition, patients with narcolepsy, who have pathologic sleepiness, are deficient in orexin. There are two orexin neuropeptides, orexin-A and orexin-B, 121 and suvorexant reversibly binds to both receptors, thereby inhibiting activation of the arousal system. 122 It is thought to be effective in patients who have difficulty initiating (sleep onset insomnia) or difficulty staying asleep (sleep maintenance insomnia).…”

“…[120][121][122][123][124][125][126][127][128] In one of the earlier double blind placebo controlled trials, various doses of suvorexant were assessed. 123 Patients received a set dose of suvorexant during a four week period and placebo in another four week period.…”

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

“…[1][2][3] The underlying mechanism of DORAs is the inhibition of orexin 1a nd orexin 2r eceptors (OX 1 Ra nd OX 2 R) to promote sleepb yr educing wakefulness. The causes of this phenomenon can be manifold.…”

Mechanism of action of suvorexant

“…1-3 Reversible pharmacologic blockade of orexin receptors is now proven to be a novel hypnotic mechanism ( Figure 4). [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Other potential clinical applications, based on preclinical studies, could eventually include use for weight loss or drug abuse. 1,4,6,7,12 Dual orexin receptor antagonists (DORAs) that block both orexin 1 and 2 receptors, and single orexin receptor antagonists (SORA-1s and SORA-2s) that selectively block either orexin 1 receptors or orexin 2 receptors, have also been developed ( Figure 4) and are being extensively tested at this time.…”

“…[1][2][3] The novel DORA suvorexant is now an approved hypnotic that improves both the initiation and maintenance of sleep in human subjects, without the side effects expected of a benzodiazepine or Z drug hypnotic, namely, dependence, withdrawal, rebound, unsteady gait, falls, confusion, amnesia, or respiratory depression. [1][2][3][12][13][14][15][16] Figure 2. Hypocretin/orexin neurotransmission is mediated by 2 types of postsynaptic G-protein-coupled receptors, orexin 1 (Ox1R) and orexin 2 (Ox2R).…”