Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist

ChemMedChem. 2013 Jun;8(6):898-903. doi: 10.1002/cmdc.201300003. Epub 2013 Apr 15.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzeneacetamides / administration & dosage
  • Benzeneacetamides / blood
  • Benzeneacetamides / pharmacology*
  • Brain / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Isoquinolines / administration & dosage
  • Isoquinolines / blood
  • Isoquinolines / pharmacology*
  • Orexin Receptor Antagonists*
  • Orexin Receptors / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • 2-(1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-isopropyl-2-phenylacetamide
  • Benzeneacetamides
  • Isoquinolines
  • Orexin Receptor Antagonists
  • Orexin Receptors