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

Abstract

Abstract: Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX₁R) and orexin 2 receptor (OX₂R) 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 OX₁R and OX₂R 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 OX₂R 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.

Keywords::

• hypocretin
• insomnia
• orexin
• pharmacology
• therapy
• MK-4305

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Corrigendum

ACKNOWLEDGMENTS

The authors would like to acknowledge Jacquelyn Binns, Joe Bruno, John Majercak, and Wei Lemaire for their contributions to the manuscript.

Declaration of interest: All authors are employees of Merck & Co., Inc. (USA) and potentially own stock and/or stock options in the company.