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The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold

BACKGROUND: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, poten...

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Autores principales: Gotter, Anthony L, Winrow, Christopher J, Brunner, Joseph, Garson, Susan L, Fox, Steven V, Binns, Jacquelyn, Harrell, Charles M, Cui, Donghui, Yee, Ka Lai, Stiteler, Mark, Stevens, Joanne, Savitz, Alan, Tannenbaum, Pamela L, Tye, Spencer J, McDonald, Terrence, Yao, Leon, Kuduk, Scott D, Uslaner, Jason, Coleman, Paul J, Renger, John J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765993/
https://www.ncbi.nlm.nih.gov/pubmed/23981345
http://dx.doi.org/10.1186/1471-2202-14-90
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author Gotter, Anthony L
Winrow, Christopher J
Brunner, Joseph
Garson, Susan L
Fox, Steven V
Binns, Jacquelyn
Harrell, Charles M
Cui, Donghui
Yee, Ka Lai
Stiteler, Mark
Stevens, Joanne
Savitz, Alan
Tannenbaum, Pamela L
Tye, Spencer J
McDonald, Terrence
Yao, Leon
Kuduk, Scott D
Uslaner, Jason
Coleman, Paul J
Renger, John J
author_facet Gotter, Anthony L
Winrow, Christopher J
Brunner, Joseph
Garson, Susan L
Fox, Steven V
Binns, Jacquelyn
Harrell, Charles M
Cui, Donghui
Yee, Ka Lai
Stiteler, Mark
Stevens, Joanne
Savitz, Alan
Tannenbaum, Pamela L
Tye, Spencer J
McDonald, Terrence
Yao, Leon
Kuduk, Scott D
Uslaner, Jason
Coleman, Paul J
Renger, John J
author_sort Gotter, Anthony L
collection PubMed
description BACKGROUND: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action. RESULTS: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX(2)R) occupancies in the range of 65 to 80%. In rats, the time course of OX(2)R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. CONCLUSION: The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.
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spelling pubmed-37659932013-09-08 The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold Gotter, Anthony L Winrow, Christopher J Brunner, Joseph Garson, Susan L Fox, Steven V Binns, Jacquelyn Harrell, Charles M Cui, Donghui Yee, Ka Lai Stiteler, Mark Stevens, Joanne Savitz, Alan Tannenbaum, Pamela L Tye, Spencer J McDonald, Terrence Yao, Leon Kuduk, Scott D Uslaner, Jason Coleman, Paul J Renger, John J BMC Neurosci Research Article BACKGROUND: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action. RESULTS: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX(2)R) occupancies in the range of 65 to 80%. In rats, the time course of OX(2)R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. CONCLUSION: The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses. BioMed Central 2013-08-28 /pmc/articles/PMC3765993/ /pubmed/23981345 http://dx.doi.org/10.1186/1471-2202-14-90 Text en Copyright © 2013 Gotter et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Gotter, Anthony L
Winrow, Christopher J
Brunner, Joseph
Garson, Susan L
Fox, Steven V
Binns, Jacquelyn
Harrell, Charles M
Cui, Donghui
Yee, Ka Lai
Stiteler, Mark
Stevens, Joanne
Savitz, Alan
Tannenbaum, Pamela L
Tye, Spencer J
McDonald, Terrence
Yao, Leon
Kuduk, Scott D
Uslaner, Jason
Coleman, Paul J
Renger, John J
The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title_full The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title_fullStr The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title_full_unstemmed The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title_short The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
title_sort duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765993/
https://www.ncbi.nlm.nih.gov/pubmed/23981345
http://dx.doi.org/10.1186/1471-2202-14-90
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