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Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist
Author(s) -
Boss Christoph,
RochBrisbare Catherine,
Steiner Michel A.,
Treiber Alexander,
Dietrich Hendrik,
Jenck Francois,
von Raumer Markus,
Sifferlen Thierry,
Brotschi Christine,
Heidmann Bibia,
Williams Jodi T.,
Aissaoui Hamed,
Siegrist Romain,
Gatfield John
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402258
Subject(s) - orexin , orexin receptor , wakefulness , narcolepsy , neuroscience , orexin a , lateral hypothalamus , pharmacology , receptor , chemistry , antagonist , medicine , psychology , hypothalamus , neuropeptide , neurology , electroencephalography
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.