title: The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species.
abstract: 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.
authors.affiliation: Department of Neurobiology, Merck & Co. Inc., Kenilworth, NJ 07033, USA.
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Lu
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hodgson
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.forename: Robert A
authors.initials: RA
authors.lastname: Del Vecchio
authors.forename: Donald H
authors.initials: DH
authors.lastname: Guthrie
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kazdoba
authors.forename: Martha F
authors.initials: MF
authors.lastname: McCool
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Morgan
authors.forename: Ana
authors.initials: A
authors.lastname: Bercovici
authors.forename: Ginny D
authors.initials: GD
authors.lastname: Ho
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D055786:Gene Knockout Techniques; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D045442:Rotarod Performance Test; D013045:Species Specificity; D014828:Vocalization, Animal / Q000187:drug effects; D000094942:Nociceptin Receptor
chemical_list: D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; D011957:Receptors, Opioid; C561126:SCH 655842; D000094942:Nociceptin Receptor