title: Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors.
abstract: Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP-/-mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Rorick-Kehn
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Benvenga
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Adams
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gleason
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Knitowski
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Steven
authors.initials: S
authors.lastname: Chaney
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Julie F
authors.initials: JF
authors.lastname: Falcone
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom.
authors.forename: Janice W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Foss
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom.
authors.forename: Kirsti
authors.initials: K
authors.lastname: Lloyd
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Kjell A
authors.initials: KA
authors.lastname: Svensson
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Toledo
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Diaz
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Lafuente
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Alma
authors.initials: A
authors.lastname: Jiménez
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Benito
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Conception
authors.initials: C
authors.lastname: Pedregal
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Martínez-Grau
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom.
authors.forename: Anke
authors.initials: A
authors.lastname: Post
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Rutgers-Robert Wood Johnson Medical School New Brunswick New Jersey.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ansonoff
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Rutgers-Robert Wood Johnson Medical School New Brunswick New Jersey.
authors.forename: John E
authors.initials: JE
authors.lastname: Pintar
authors.affiliation: Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
keywords: Antidepressant; LY2940094; anxiolytic; nociceptin