| Autor: |
Witkin JM; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Rorick-Kehn LM; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Benvenga MJ; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Adams BL; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Gleason SD; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Knitowski KM; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Li X; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Chaney S; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Falcone JF; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Smith JW; Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom., Foss J; Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom., Lloyd K; Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom., Catlow JT; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., McKinzie DL; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Svensson KA; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Barth VN; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana., Toledo MA; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Diaz N; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Lafuente C; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Jiménez A; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Benito A; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Pedregal C; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Martínez-Grau MA; Lilly Research Laboratories Eli Lilly and Company Alcobendas Madrid Spain., Post A; Lilly Research Laboratories Eli Lilly and Company Windlesham Surrey United Kingdom., Ansonoff MA; Lilly Research Laboratories Eli Lilly and Company Rutgers-Robert Wood Johnson Medical School New Brunswick New Jersey., Pintar JE; Lilly Research Laboratories Eli Lilly and Company Rutgers-Robert Wood Johnson Medical School New Brunswick New Jersey., Statnick MA; Lilly Research Laboratories Eli Lilly and Company Indianapolis Indiana. |
| Abstrakt: |
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. |
