A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects

Pascal Bonaventure, Sujin Yun, Philip Johnson, Anantha Shekhar, Stephanie D. Fitz, Brock T. Shireman, Terry P. Lebold, Diane Nepomuceno, Brian Lord, Michelle Wennerholm, Jonathan Shelton, Nicholas Carruthers, Timothy Lovenberg, Christine Dugovic

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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 wildtype 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.

Original languageEnglish
Pages (from-to)590-601
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number3
DOIs
StatePublished - Mar 1 2015

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Orexin Receptors
Hypnotics and Sedatives
Panic
Sleep
Sodium Lactate
Amines
REM Sleep
Brain
Arousal
Blood-Brain Barrier
Psychological Stress
Knockout Mice
Psychiatry
Urea
Anxiety
Orexin Receptor Antagonists
Neurons
Peptides
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. / Bonaventure, Pascal; Yun, Sujin; Johnson, Philip; Shekhar, Anantha; Fitz, Stephanie D.; Shireman, Brock T.; Lebold, Terry P.; Nepomuceno, Diane; Lord, Brian; Wennerholm, Michelle; Shelton, Jonathan; Carruthers, Nicholas; Lovenberg, Timothy; Dugovic, Christine.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 352, No. 3, 01.03.2015, p. 590-601.

Research output: Contribution to journalArticle

Bonaventure, P, Yun, S, Johnson, P, Shekhar, A, Fitz, SD, Shireman, BT, Lebold, TP, Nepomuceno, D, Lord, B, Wennerholm, M, Shelton, J, Carruthers, N, Lovenberg, T & Dugovic, C 2015, 'A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects', Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 3, pp. 590-601. https://doi.org/10.1124/jpet.114.220392
Bonaventure, Pascal ; Yun, Sujin ; Johnson, Philip ; Shekhar, Anantha ; Fitz, Stephanie D. ; Shireman, Brock T. ; Lebold, Terry P. ; Nepomuceno, Diane ; Lord, Brian ; Wennerholm, Michelle ; Shelton, Jonathan ; Carruthers, Nicholas ; Lovenberg, Timothy ; Dugovic, Christine. / A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 352, No. 3. pp. 590-601.
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