Promotion of Sleep by Suvorexant—A Novel Dual Orexin Receptor Antagonist

作者：Christopher J. Winrow, Anthony L. Gotter, Christopher D. Cox, Scott M. Doran, Pamela L. Tannenbaum, Michael J. Breslin, Susan L. Garson, Steven V. Fox, C. Meacham Harrell, Joanne Stevens, Duane R. Reiss, Donghui Cui, Paul J. Coleman, John J. Renger · 发表于：Journal of Neurogenetics · 年份：2011 · DOI：10.3109/01677063.2011.566953 · 被引用次数：270 · 研究领域：Sleep and Wakefulness Research、Sleep and related disorders、Circadian rhythm and melatonin

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.