The orexin system consists of two G-protein-coupled receptors, the orexin 1 receptor and the orexin 2 receptor, widely expressed in diverse regions of the brain and two peptide agonists orexin A and orexin B, which are expressed in a small assembly of neurons in the lateral hypothalamus. [1] The orexin system plays an important role in the regulation of sleep and wakefulness and particularly for the appropriate maintenance of wakefulness across a variety of conditions. Several compounds (almorexant, suvorexant) have been in advanced clinical trials for primary insomnia. [2, 3] ACT-462206 is a new, potent, and selective dual orexin receptor antagonist that inhibits the stimulating effects of the orexin A or B peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-REM and REM sleep while maintaining natural sleep patterns in rat and dog EEG experiments. It is therefore a potential candidate for the treatment of insomnia.  Fig 1:  Structure of the Dual Proline Sulfonamide Orexin Receptor Antagonist ACT-462206

Structure-activity-relationship, biological and pharmacological characterization of the proline sulfonamide ACT-462206, a highly potent, brain penetrant dual orexin 1/orexin 2 receptor antagonist

248th National Meeting (2014)

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