Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist

J Neurogenet. 2011 Mar;25(1-2):52-61. doi: 10.3109/01677063.2011.566953. Epub 2011 Apr 8.

Abstract

Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 μM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.

MeSH terms

  • Animals
  • Area Under Curve
  • Azepines / pharmacology*
  • Azides
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Electromyography
  • Humans
  • Macaca mulatta
  • Motor Activity / drug effects
  • Octreotide / analogs & derivatives
  • Orexin Receptors
  • Protein Binding / drug effects
  • Rats
  • Reaction Time / drug effects
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / genetics
  • Receptors, Neuropeptide / metabolism
  • Sleep / drug effects*
  • Transfection
  • Triazoles / pharmacology*

Substances

  • Azepines
  • Azides
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Triazoles
  • suvorexant
  • EE 581
  • Octreotide