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

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.

• Authors: Christopher J Winrow, Anthony L Gotter, Christopher D Cox, Scott M Doran, Pamela L Tannenbaum, Michael J Breslin, Susan L Garson, Steven V Fox, Charles M Harrell, Joanne Stevens, Duane R Reiss, Donghui Cui, Paul J Coleman, John J Renger
• Journal: Journal of neurogenetics (J Neurogenet) Vol. 25 Issue 1-2 Pg. 52-61 (Mar 2011) ISSN: 1563-5260 [Electronic] England
• PMID: 21473737 (Publication Type: Journal Article)

Chemical References

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

Topics

• 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, genetics, metabolism)
• Receptors, Neuropeptide (antagonists & inhibitors, genetics, metabolism)
• Sleep (drug effects)
• Transfection
• Triazoles (pharmacology)