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

Anthony L. Gotter; Mark S. Forman; Charles M. Harrell; Joanne Stevens; Vladimir Svetnik; Ka Lai Yee; Xiaodong Li; Anthony J. Roecker; Steven V. Fox; Pamela L. Tannenbaum; Susan L. Garson; Inge De Lepeleire; Nicole Calder; Laura Rosen; Arie Struyk; Paul J. Coleman; W. Joseph Herring; John J. Renger; Christopher J. Winrow

doi:10.1038/srep27147

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

Anthony L. Gotter, Mark S. Forman, Charles M. Harrell, Joanne Stevens, Vladimir Svetnik, Ka Lai Yee, Xiaodong Li, Anthony J. Roecker, Steven V. Fox, Pamela L. Tannenbaum, Susan L. Garson, Inge De Lepeleire, Nicole Calder, Laura Rosen, Arie Struyk, Paul J. Coleman, W. Joseph Herring, John J. Renger, Christopher J. Winrow

Research output: Contribution to journal › Article › peer-review

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Abstract

Orexin neuropeptides regulate sleep/wake through orexin receptors (OX₁R, OX₂R); OX₂R is the predominant mediator of arousal promotion. The potential for single OX₂ R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX₂ R-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.

Original language	English (US)
Article number	27147
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep27147
State	Published - Jun 3 2016
Externally published	Yes

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Gotter, A. L., Forman, M. S., Harrell, C. M., Stevens, J., Svetnik, V., Yee, K. L., Li, X., Roecker, A. J., Fox, S. V., Tannenbaum, P. L., Garson, S. L., De Lepeleire, I., Calder, N., Rosen, L., Struyk, A., Coleman, P. J., Herring, W. J., Renger, J. J., & Winrow, C. J. (2016). Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man. Scientific Reports, 6, [27147]. https://doi.org/10.1038/srep27147

Gotter, AL, Forman, MS, Harrell, CM, Stevens, J, Svetnik, V, Yee, KL, Li, X, Roecker, AJ, Fox, SV, Tannenbaum, PL, Garson, SL, De Lepeleire, I, Calder, N, Rosen, L, Struyk, A, Coleman, PJ, Herring, WJ, Renger, JJ & Winrow, CJ 2016, 'Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man', Scientific Reports, vol. 6, 27147. https://doi.org/10.1038/srep27147

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title = "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 OX2 R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2 R-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.",

author = "Gotter, {Anthony L.} and Forman, {Mark S.} and Harrell, {Charles M.} and Joanne Stevens and Vladimir Svetnik and Yee, {Ka Lai} and Xiaodong Li and Roecker, {Anthony J.} and Fox, {Steven V.} and Tannenbaum, {Pamela L.} and Garson, {Susan L.} and {De Lepeleire}, Inge and Nicole Calder and Laura Rosen and Arie Struyk and Coleman, {Paul J.} and Herring, {W. Joseph} and Renger, {John J.} and Winrow, {Christopher J.}",

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doi = "10.1038/srep27147",

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AU - Gotter, Anthony L.

AU - Forman, Mark S.

AU - Harrell, Charles M.

AU - Stevens, Joanne

AU - Svetnik, Vladimir

AU - Yee, Ka Lai

AU - Li, Xiaodong

AU - Roecker, Anthony J.

AU - Fox, Steven V.

AU - Tannenbaum, Pamela L.

AU - Garson, Susan L.

AU - De Lepeleire, Inge

AU - Calder, Nicole

AU - Rosen, Laura

AU - Struyk, Arie

AU - Coleman, Paul J.

AU - Herring, W. Joseph

AU - Renger, John J.

AU - Winrow, Christopher J.

PY - 2016/6/3

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N2 - Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2 R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2 R-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.

AB - Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2 R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2 R-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.

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

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