Article

Almorexant, a dual orexin receptor antagonist for the treatment of insomnia

Johns Hopkins Bayview Medical Center, Department of Psychiatry, 4940 Eastern Avenue, Box 151, Baltimore, MD 21224, USA.
Current opinion in investigational drugs (London, England: 2000) (Impact Factor: 3.55). 01/2010; 11(1):101-10.
Source: PubMed

ABSTRACT

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.

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    • "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 [208], and thus the assessment of effects of such compounds in schizophrenia patients in future studies is warranted. "
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    • "The orexin system has been implicated in numerous physiological functions, including energy homeostasis, feeding and reward, regulation of arousal, and the sleepwake cycle (Kilduff and Peyron, 2000; Ohno and Sakurai, 2008). Preclinical (canine and rat) and clinical (healthy male subjects; single dose) investigations have shown that almorexant, when administered orally during the active period, promoted sleep in animals and humans without disrupting the sleep architecture or inducing cataplexy (Brisbare-Roch et al., 2007; Neubauer, 2010), thereby further validating the involvement of orexin system in the regulation of alertness and sleep. Thus, OX antagonists represent an alternative therapeutic approach for the treatment of insomnia (Nishino, 2007; Roecker and Coleman, 2008; Boss et al., 2009). "
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    ABSTRACT: The orexins and their receptors are involved in the regulation of arousal and sleep-wake cycle. Clinical investigation with almorexant has indicated that this dual OX antagonist is efficacious in inducing and maintaining sleep. Using site-directed mutagenesis, beta(2)-adrenergic-based OX(1) and OX(2) modeling, we have determined important molecular determinants of the ligand-binding pocket of OX(1) and OX(2). The conserved residues Asp(45.51), Trp(45.54), Tyr(5.38), Phe(5.42), Tyr(5.47), Tyr(6.48), and His(7.39) were found to be contributing to both orexin-A-binding sites at OX(1) and OX(2). Among these critical residues, five (positions 45.51, 45.54, 5.38, 5.42, and 7.39) were located on the C-terminal strand of the second extracellular loop (ECL2b) and in the top of TM domains at the interface to the main binding crevice, thereby suggesting superficial OX receptor interactions of orexin-A. We found that the mutations W214A(45.54), Y223A(5.38), F227A(5.42), Y317A(6.48), and H350A(7.39) resulted in the complete loss of both [(3)H]almorexant and [(3)H]N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA) binding affinities and also blocked their inhibition of orexin-A-evoked [Ca(2+)](i) response at OX(2). The crucial residues Gln126(3.32), Ala127(3.33), Trp206(45.54), Tyr215(5.38), Phe219(5.42), and His344(7.39) are shared between almorexant and 1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone (SB-674042) binding sites in OX(1). The nonconserved residue at position 3.33 of orexin receptors was identified as occupying a critical position that must be involved in subtype selectivity and also in differentiating two different antagonists for the same receptor. In summary, despite high similarities in the ligand-binding pockets of OX(1) and OX(2) and numerous aromatic/hydrophobic interactions, the local conformation of helix positions 3.32, 3.33, and 3.36 in transmembrane domain 3 and 45.51 in ECL2b provide the structural basis for pharmacologic selectivity between OX(1) and OX(2).
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