Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist. Issue 11 (21st August 2014) - Boss, Christoph
Abstract The orexin system consists of two G‐protein‐coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB‐649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT‐462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non‐rapid eye movement (non‐REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT‐462206 shows anxiolytic‐like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.