PT  - JOURNAL ARTICLE
AU  - Carsten Theodor Beuckmann
AU  - Michiyuki Suzuki
AU  - Takashi Ueno
AU  - Kazuya Nagaoka
AU  - Tohru Arai
AU  - Hiroyuki Higashiyama
TI  - In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist
AID  - 10.1124/jpet.117.241422
DP  - 2017 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 287--295
VI  - 362
IP  - 2
4099  - http://jpet.aspetjournals.org/content/362/2/287.short
4100  - http://jpet.aspetjournals.org/content/362/2/287.full
SO  - J Pharmacol Exp Ther2017 Aug 01; 362
AB  - Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the π-stacked horseshoe-like conformation.