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Research ArticleDrug Discovery and Translational Medicine

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Pascal Bonaventure, Sujin Yun, Philip L. Johnson, Anantha Shekhar, Stephanie D. Fitz, Brock T. Shireman, Terry P. Lebold, Diane Nepomuceno, Brian Lord, Michelle Wennerholm, Jonathan Shelton, Nicholas Carruthers, Timothy Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics March 2015, 352 (3) 590-601; DOI: https://doi.org/10.1124/jpet.114.220392
Pascal Bonaventure
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Sujin Yun
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Philip L. Johnson
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Anantha Shekhar
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Stephanie D. Fitz
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Brock T. Shireman
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Terry P. Lebold
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Diane Nepomuceno
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Brian Lord
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Michelle Wennerholm
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Jonathan Shelton
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Nicholas Carruthers
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Timothy Lovenberg
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Christine Dugovic
Janssen Research & Development, LLC, San Diego, California (P.B., S.Y., B.T.S., T.P.L., D.N., B.L., M.W., J.S., N.C., T.L., C.D.); and Indiana University School of Medicine, Indianapolis, Indiana (P.L.J., A.S., S.D.F.)
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Abstract

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine]. Ex vivo receptor binding studies demonstrated that, after subcutaneous administration, compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain at lower doses than standard OX1R antagonists GSK-1059865 [5-bromo-N-({1-[(3-fluoro-2-methoxyphenyl)carbonyl]-5-methylpiperidin-2-yl}methyl)pyridin-2-amine], SB-334867 [1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea], and SB-408124 [1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea]. Although compound 56 did not alter spontaneous sleep in rats and in wild-type mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate–induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

Footnotes

    • Received October 7, 2014.
    • Accepted January 9, 2015.
  • This work was supported by Janssen Research and Development, LLC; the National Institutes of Health National Institute on Aging [Grant 1K01-AG044466-01A1]; National Institutes of Health National Center for Research Resources [Grant UL1-RR025761] (to P.L.J.); and the National Institutes of Health National Institute of Mental Health [Grant R01-MH52619 and R01-MH65702] (to A.S.).

  • dx.doi.org/10.1124/jpet.114.220392.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 3
1 Mar 2015
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Research ArticleDrug Discovery and Translational Medicine

Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal

Pascal Bonaventure, Sujin Yun, Philip L. Johnson, Anantha Shekhar, Stephanie D. Fitz, Brock T. Shireman, Terry P. Lebold, Diane Nepomuceno, Brian Lord, Michelle Wennerholm, Jonathan Shelton, Nicholas Carruthers, Timothy Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 590-601; DOI: https://doi.org/10.1124/jpet.114.220392

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Research ArticleDrug Discovery and Translational Medicine

Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal

Pascal Bonaventure, Sujin Yun, Philip L. Johnson, Anantha Shekhar, Stephanie D. Fitz, Brock T. Shireman, Terry P. Lebold, Diane Nepomuceno, Brian Lord, Michelle Wennerholm, Jonathan Shelton, Nicholas Carruthers, Timothy Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 590-601; DOI: https://doi.org/10.1124/jpet.114.220392
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