Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors

Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors

Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of act...

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Main Authors: Callander, Gabrielle E., Olorunda, Morenike, Monna, Dominique, Schuepbach, Edi, Langenegger, Daniel, Betschart, Claudia, Hintermann, Samuel, Behnke, Dirk, Cotesta, Simona, Fendt, Markus, Laue, Grit, Ofner, Silvio, Briard, Emmanuelle, Gee, Christine E., Jacobson, Laura H., Hoyer, Daniel
Format: Online
Language:English
Published: Frontiers Media S.A. 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847553/
id pubmed-3847553
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spelling pubmed-38475532013-12-27 Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors Callander, Gabrielle E. Olorunda, Morenike Monna, Dominique Schuepbach, Edi Langenegger, Daniel Betschart, Claudia Hintermann, Samuel Behnke, Dirk Cotesta, Simona Fendt, Markus Laue, Grit Ofner, Silvio Briard, Emmanuelle Gee, Christine E. Jacobson, Laura H. Hoyer, Daniel Pharmacology Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various “dual” orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [3H]-BBAC ((S)-N-([1,1′-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the “dual” antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the “dual” antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo. Frontiers Media S.A. 2013-12-03 /pmc/articles/PMC3847553/ /pubmed/24376396 http://dx.doi.org/10.3389/fnins.2013.00230 Text en Copyright © 2013 Callander, Olorunda, Monna, Schuepbach, Langenegger, Betschart, Hintermann, Behnke, Cotesta, Fendt, Laue, Ofner, Briard, Gee, Jacobson and Hoyer. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Callander, Gabrielle E.
Olorunda, Morenike
Monna, Dominique
Schuepbach, Edi
Langenegger, Daniel
Betschart, Claudia
Hintermann, Samuel
Behnke, Dirk
Cotesta, Simona
Fendt, Markus
Laue, Grit
Ofner, Silvio
Briard, Emmanuelle
Gee, Christine E.
Jacobson, Laura H.
Hoyer, Daniel
spellingShingle Callander, Gabrielle E.
Olorunda, Morenike
Monna, Dominique
Schuepbach, Edi
Langenegger, Daniel
Betschart, Claudia
Hintermann, Samuel
Behnke, Dirk
Cotesta, Simona
Fendt, Markus
Laue, Grit
Ofner, Silvio
Briard, Emmanuelle
Gee, Christine E.
Jacobson, Laura H.
Hoyer, Daniel
Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
author_facet Callander, Gabrielle E.
Olorunda, Morenike
Monna, Dominique
Schuepbach, Edi
Langenegger, Daniel
Betschart, Claudia
Hintermann, Samuel
Behnke, Dirk
Cotesta, Simona
Fendt, Markus
Laue, Grit
Ofner, Silvio
Briard, Emmanuelle
Gee, Christine E.
Jacobson, Laura H.
Hoyer, Daniel
author_sort Callander, Gabrielle E.
title Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
title_short Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
title_full Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
title_fullStr Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
title_full_unstemmed Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
title_sort kinetic properties of “dual” orexin receptor antagonists at ox1r and ox2r orexin receptors
description Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various “dual” orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [3H]-BBAC ((S)-N-([1,1′-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the “dual” antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the “dual” antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.
publisher Frontiers Media S.A.
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847553/
_version_ 1612033045284519936

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