title: A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat.
abstract: The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound [(1S,3aS)-8- (2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza- spiro[4. 5]decan-4-one] has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg/kg i.p.). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (>/=10 mg/kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ/nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ/nociceptin in adaptive behavioral fear responses to stress.
authors.affiliation: Central Nervous System Research, Roche Pharma Division, CH4070 Basel, Switzerland. francois.jenck@roche.com
authors.forename: F
authors.initials: F
authors.lastname: Jenck
authors.forename: J
authors.initials: J
authors.lastname: Wichmann
authors.forename: F M
authors.initials: FM
authors.lastname: Dautzenberg
authors.forename: J L
authors.initials: JL
authors.lastname: Moreau
authors.forename: A M
authors.initials: AM
authors.lastname: Ouagazzal
authors.forename: J R
authors.initials: JR
authors.lastname: Martin
authors.forename: K
authors.initials: K
authors.lastname: Lundstrom
authors.forename: A M
authors.initials: AM
authors.lastname: Cesura
authors.forename: S M
authors.initials: SM
authors.lastname: Poli
authors.forename: S
authors.initials: S
authors.lastname: Roever
authors.forename: S
authors.initials: S
authors.lastname: Kolczewski
authors.forename: G
authors.initials: G
authors.lastname: Adam
authors.forename: G
authors.initials: G
authors.lastname: Kilpatrick
mesh_terms: D000161:Acoustic Stimulation; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000503:physiopathology; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D012653:Self Stimulation / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: D014151:Anti-Anxiety Agents; D007093:Imidazoles; D011957:Receptors, Opioid; D011994:Recombinant Proteins; C408068:Ro 64-6198; D013141:Spiro Compounds; D003975:Diazepam; D010433:Pentylenetetrazole; D000525:Alprazolam; D000094942:Nociceptin Receptor