Almorexant, a dual orexin receptor antagonist for the treatment of 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. 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. Decreasing orexin activity was hypothesized to have a sleep-promoting effect. Preclinical studies and phase I clinical trials have demonstrated that almorexant decreases alertness and increases sleep in healthy rats, dogs and humans when administered during the active phase of the circadian cycle, at peak endogenous orexin tone. No significant toxicological or safety concerns have been identified in studies in animals and humans, including no evidence of cataplexy, a sudden postural muscle tone weakening that is triggered by emotional stimuli and is considered unique to narcolepsy. The reported efficacy and safety data for almorexant support the continued development of the compound. At the time of publication, phase III clinical trials were underway, but no results had been reported; Actelion and GlaxoSmithKline were also investigating almorexant for other orexin-related neurological disorders. The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits.
[Show abstract] [Hide abstract] ABSTRACT: Orexins (also known as hypocretins) play critical roles in the regulation of sleep/wakefulness states by activating two G-protein coupled receptors (GPCRs), orexin 1 (OX1R) and orexin 2 receptors (OX2R). In order to understand the differential contribution of both receptors in regulating sleep/wakefulness states we compared the pharmacological effects of a newly developed OX2R antagonist (2-SORA), Compound 1 m (C1 m), with those of a dual orexin receptor antagonist (DORA), suvorexant, in C57BL/6J mice. After oral administration in the dark period, both C1m and suvorexant decreased wakefulness time with similar efficacy in a dose-dependent manner. While C1m primarily increased total non-rapid eye movement (NREM) sleep time without affecting episode durations and with minimal effects on REM sleep, suvorexant increased both total NREM and REM sleep time and episode durations with predominant effects on REM sleep. Fos-immunostaining showed that both compounds affected the activities of arousal-related neurons with different patterns. The number of Fos-IR noradrenergic neurons in the locus coeruleus was lower in the suvorexant group as compared with the control and C1m-treated groups. In contrast, the numbers of Fos-IR neurons in histaminergic neurons in the tuberomamillary nucleus and serotonergic neurons in the dorsal raphe were reduced to a similar extent in the suvorexant and C1m groups as compared with the vehicle-treated group. Together, these results suggest that an orexin-mediated suppression of REM sleep via potential activation of OX1Rs in the locus coeruleus may possibly contribute to the differential effects on sleep/wakefulness exerted by a DORA as compared to a 2-SORA.0Comments 13Citations
- "In addition, it was reported that rats administered a high dose of almorexant (300 mg/kg, p.o.) were fully capable of spatial and avoidance learning (Dietrich and Jenck, 2010). Notably, almorexant was well tolerated with no sign of cataplexy, suggesting that acute, short-lived, intermittent temporary blockade of orexin receptors will not result in a narcolepsy-like phenotype (Neubauer, 2010). Phase III clinical trials of suvorexant (MK-4305), a DORA developed by Merck & Co., for the modulation of sleep have been completed (Cox et al., 2010). "
[Show abstract] [Hide abstract] ABSTRACT: This review explores basic sleep physiology, the mechanism of action for each class of hypnotic agents, their clinical application based on pharmacodynamic and pharmacokinetic factors, and potential pharmacologic sleep-inducing mechanisms of future hypnotics. The paper challenges the reader to understand the neuroscientific basis of insomnia and use this knowledge to guide prescription of hypnotic agents. Currently indicated hypnotic agents are discussed with regard to their mechanism of drug action and clinical application. A broader discussion is developed throughout this paper regarding other non-indicated agents that may improve sleep and describing newer pharmacological treatments that may become available in the future for use in sleep disorders and their comorbid conditions.0Comments 3Citations
- "It follows that removing orexin activity by blocking OX1/2 receptors may produce onset of sleep . Preliminary studies had shown that this agent was potentially effective in treating insomnia but development has recently ceased due to safety concerns [36, 39]. Other antagonists appear to be in development however. "
[Show abstract] [Hide abstract] ABSTRACT: Schizophrenia affects approximately 1% of the world population, and the majority of pharmacologically based treatments for this disorder are ligands that interact with monoaminergic transmission. However, there is a wealth of evidence that various neuropeptides are often co-released with monoamine neurotransmitters, and that ligands acting at neuropeptide receptors modulate monoaminergic transmission as well as schizophrenia-related behaviors in preclinical animal models. Such neuropeptide systems include neurotensin, cholecystokinin, corticotropin releasing factor, neuropeptide Y, oxytocin, opioid peptides, tachykinins, thyrotropin-releasing hormone, and orexins. The purpose of this review will be to summarize the existing preclinical and clinical literature on the role of various neuropeptide systems as modulators of schizophrenia-related behaviors, and the potential of targeting these systems for the development of novel antipsychotic medications.0Comments 12Citations
- "While the aforementioned studies provide some evidence that modafinil might be of potential use as an adjunctive therapy in some schizophrenia patients, the murky neurochemical mechanism of action of modafinil makes it difficult to ascertain whether any potential effects might be related to its actions on the orexin system. However, recently orexin receptor ligands such as almorexant has advanced to clinical trials , and thus the assessment of effects of such compounds in schizophrenia patients in future studies is warranted. "