The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]oct a ne-3-carboxamide (SCH 655842): Comparison of efficacy and side effects across rodent species

• Published in: European journal of pharmacology Vol. 661; no. 1-3; pp. 63 - 71
• Main Authors: Lu, Sherry X, Higgins, Guy A, Hodgson, Robert A, Hyde, Lynn A, Del Vecchio, Robert A, Guthrie, Donald H, Kazdoba, Tatiana, McCool, Martha F, Morgan, Cynthia A, Bercovici, Ana, Ho, Ginny D, Tulshian, Deen, Parker, Eric M, Hunter, John C, Varty, Geoffrey B
• Format: Journal Article
• Language: English
• Published: 01.07.2011
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2011.04.034

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.