title: A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects.
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.
authors.affiliation: 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.) Pbonave1@its.jnj.com CDugovic@its.jnj.com.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.affiliation: 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.).
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
authors.affiliation: 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.).
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.affiliation: 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.).
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.affiliation: 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.).
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.affiliation: 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.).
authors.forename: Brock T
authors.initials: BT
authors.lastname: Shireman
authors.affiliation: 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.).
authors.forename: Terry P
authors.initials: TP
authors.lastname: Lebold
authors.affiliation: 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.).
authors.forename: Diane
authors.initials: D
authors.lastname: Nepomuceno
authors.affiliation: 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.).
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: 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.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Wennerholm
authors.affiliation: 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.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shelton
authors.affiliation: 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.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Carruthers
authors.affiliation: 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.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Lovenberg
authors.affiliation: 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.).
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
mesh_terms: D000631:Aminopyridines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: C559922:5-bromo-N-(1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl)methylpyridin-2-amine; D000631:Aminopyridines; D006993:Hypnotics and Sedatives; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines