Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

Abstract

Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual orexin receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual orexin receptor antagonism.

Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications

“…This raises the question as to whether 2‐SORAs might offer efficacy and/or tolerability advantages over DORAs such as suvorexant. In a Phase 1 study in healthy subjects, the 2‐SORA MK‐1064 demonstrated dose‐dependent increases in subjective and objective sleep measures, including increased REM and NREM sleep similar to that seen with suvorexant (Gotter et al., ). Another 2‐SORA, seltorexant (MIN‐202/JNJ‐42847922; Bonaventure, Shelton, et al., ), has been evaluated in early phase clinical trials of patients with insomnia, but to date those results are unpublished (NCT02464046; NCT02067299).…”

“…This suggests that the wake‐suppressing effects of ORAs are due, at least in part, to the inhibition of OX2R‐dependent histamine release from tuberomammillary nuclei (Schone & Burdakov, ; Yao et al., ). In support of this, 2‐SORAs have sleep‐promoting effects while 1‐SORAs do not (Gotter et al., ; Jacobson, Chen, Mir, & Hoyer, ). Brainstem nuclei containing OX1R (including the locus coeruleus and pedunculopontine and laterodorsal tegmental nuclei, which receive projections of orexin neurons) may be involved in transitions between vigilance states (Sakurai, ).…”

“…Brainstem nuclei containing OX1R (including the locus coeruleus and pedunculopontine and laterodorsal tegmental nuclei, which receive projections of orexin neurons) may be involved in transitions between vigilance states (Sakurai, ). There is also some evidence that 2‐SORAs may require higher receptor occupancy to achieve similar sleep maintenance to a DORA, which would suggest that OX1R has some role in sleep maintenance (Gotter et al., ). Overall, OX2R has a clear role in sleep/wake regulation, while the role of OX1R is less well defined (Coleman et al., ).…”

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

“…Intense research led to compounds currently investigated in late stage clinical trials for the treatment of insomnia, e. g. lemborexant ( 2 ) from Eisai or daridorexant ( 3 ) from Idorsia, both DORA's inhibiting orexin 1 and orexin 2 receptors (OX 1 R and OX 2 R, respectively). Seltorexant ( 4 ), a selective OX 2 R antagonist co‐developed by Janssen and Minerva Neurosciences is as well in clinical development for the treatment of insomnia . The therapeutic potential of selective OX 1 R antagonists is also investigated such as SB‐334867 ( 5 ) from GlaxoSmithKline, JNJ‐61393215 from Janssen, and ACT‐539313 from Idorsia.…”

Improved sleep scoring in mice reveals human-like stages

“…Despite their clinical relevance, the different stages of NREM sleep have never been considered in experimental research on rodents. In pharmacological studies designed to characterize the efficiency of drugs on sleep, results in human showed that drugs affect the different substages of sleep in a specific manner but fail to provide the same specificity in rodent, and only address global measure of sleep (Brisbare-Roch et al, 2007;Gotter et al, 2016). The main limit is the rather vague or inappropriate definition of the NREM sleep in rodent that precludes efficient translational study, even though the pharmacology of vigilance states perturbations is very similar between those species (Toth and Bhargava, 2013).…”