Preclinical findings predicting efficacy and side‐effect profile of LY 2940094, an antagonist of nociceptin receptors
Year: 2016
Type: article
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.
DOI: 10.1002/prp2.275
Authors: 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 Jiménez, Alfonso Benito, Conception Pedregal, Maria A. Martínez‐Grau, Anke Post, Michael A. Ansonoff, John E. Pintar, Michael A. Statnick
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,160
Funder: Eli Lilly and Company
OpenAlex ID: W2549617707