title: Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist.
abstract: Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats.
authors.affiliation: Actelion Pharmaceuticals Ltd. Gewerbestrasse 16, 4123 Allschwil, Switzerland. michel.steiner@actelion.com
authors.forename: Michel A
authors.initials: MA
authors.lastname: Steiner
authors.forename: John
authors.initials: J
authors.lastname: Gatfield
authors.forename: Catherine
authors.initials: C
authors.lastname: Brisbare-Roch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dietrich
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Francois
authors.initials: F
authors.lastname: Jenck
authors.forename: Christoph
authors.initials: C
authors.lastname: Boss
mesh_terms: D000284:Administration, Oral; D000818:Animals; D044482:Benzeneacetamides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C585818:2-(1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-isopropyl-2-phenylacetamide; D044482:Benzeneacetamides; D007546:Isoquinolines; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors