Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors

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• 作者：Jeffrey M. Witkin ; Linda M. Rorick-Kehn ; Mark J. Benvenga ; Benjamin L. Adams ; Scott D. Gleason ; Karen M. Knitowski ; Xia Li ; Steven Chaney ; Julie F. Falcone ; Janice W. Smith ; Julie Foss ; Kirsti Lloyd ; John T. Catlow ; David L. McKinzie ; Kjell A. Svensson ; Vanessa N. Barth ; Miguel A. Toledo ; Nuria Diaz ; Celia Lafuente ; Alma Jim&eacute ; nez ; Alfonso Benito ; Conception Pedregal ; Maria A. Martí ; nez-Grau ; Anke Post ; Michael A. Ansonoff ; John E. Pintar and Michael A. Statnick
• 刊名：Pharmacology Research & Perspectives
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：4
• 期：6
• 全文大小：629K
• ISSN：2052-1707

文摘

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.