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.
Subject(s)
Anti-Anxiety Agents/pharmacology , Fear/physiology , Imidazoles/pharmacology , Maze Learning/drug effects , Receptors, Opioid/agonists , Reflex, Startle/drug effects , Spiro Compounds/pharmacology , Acoustic Stimulation , Alprazolam/pharmacology , Animals , Cognition/drug effects , Cognition/physiology , Conflict, Psychological , Diazepam/pharmacology , Dose-Response Relationship, Drug , Electroshock , Epilepsy/chemically induced , Epilepsy/physiopathology , Fear/drug effects , Humans , Male , Maze Learning/physiology , Pain/physiopathology , Pentylenetetrazole , Rats , Rats, Sprague-Dawley , Receptors, Opioid/physiology , Recombinant Proteins/metabolism , Seizures/chemically induced , Seizures/physiopathology , Self Stimulation/drug effects , Nociceptin ReceptorABSTRACT
Heterocyclic enol ethers of type 1 were studied with respect to the inhibition of 1S,3R-ACPD (10 microM)-stimulated GTP gamma35S binding on rat mGluR2 transfected cell membranes. The structure activity relationship with regard to the substitution pattern of the phenyl ring, the oxygen substituent and the nature of the heterocycle is discussed.
Subject(s)
Ethers/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Brain/drug effects , Brain/metabolism , Cell Membrane/drug effects , Cell Membrane/metabolism , Ethers/chemistry , Ethers/pharmacology , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Rats , Structure-Activity Relationship , Sulfur Radioisotopes , TransfectionABSTRACT
A series of 5H-thiazolo[3,2-a]pyrimidine derivatives 1 was studied with respect to the inhibition of 1S,3R-ACPD (10 microM)-stimulated GTP gamma35S binding on rat mGlu2 receptor transfected cell membranes. The influence of substituents at position 6 and 7 as well as the substitution pattern of the two phenyl-rings in position 2 and 5 on the activity is discussed.
