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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Jenck, F. Dautzenberg, F. M. Kilpatrick, G. Poli, S. M. Moreau, J. L. Lundstrom, K. Martin, J. R. Roever, S. Wichmann, J. Kolczewski, S. Ouagazzal, A. M. Adam, G. Cesura, A. M. |
| Description | Author Affiliation: Jenck F ( Central Nervous System Research, Roche Pharma Division, CH4070 Basel, Switzerland. francois.jenck@roche.com); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 9 |
| Volume Number | 97 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2000-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Anti-Anxiety Agents Pharmacology Physiology Imidazoles Maze Learning Drug Effects Receptors, Opioid Agonists Reflex, Startle Spiro Compounds Acoustic Stimulation Alprazolam Animals Cognition Conflict (Psychology) Diazepam Dose-Response Relationship, Drug Electroshock Epilepsy Chemically Induced Physiopathology Pain Pentylenetetrazole Rats, Sprague-Dawley Recombinant Proteins Metabolism Seizures Self Stimulation Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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