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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 20, 2008; DOI: 10.1124/jpet.108.136937

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Received for publication January 22, 2008.
Revised May 19, 2008.
Accepted for publication May 20, 2008.

The anxiolytic-like effects of the novel, orally active nociceptin NOP receptor agonist, 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

Geoffrey B Varty 1, Sherry X Lu 1, Cynthia A Morgan 1, Mary E Cohen-Williams 1, Robert A Hodgson 1*, April Smith-Torhan 1, Hongtao Zhang 1, Ahmad B Fawzi 1, Michael P Graziano 1, Ginny D Ho 1, Julius Matasi 1, Deen Tulshian 1, Vicki L Coffin 1, Galen J Carey 1

1 Schering-Plough Research Institute

* Address correspondence to: E-mail: robert.hodgson{at}spcorp.com

Abstract

Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present studies assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC50 = 12 nM) that binds with high affinity (Ki = 0.3 nM) and functional selectivity (>50-fold over the µ, {kappa} and {delta}-opioid receptors). The anxiolytic-like activity and side effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Additionally, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist, J-113397, and the opioid receptor antagonist, naltrexone. Like CDP (1-30 mg/kg, ip), SCH 221510 (1-30 mg/kg, po) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat) and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg, po), but not naltrexone (3-30 mg/kg, ip). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg), produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.


Key words: Anxiety Disorders, NOP, Nociceptin, Opioid, Orphanin FQ, Rodent




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