Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic.

Abstract

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.

• Authors: F Jenck, J L Moreau, E P Bonetti, J R Martin, W E Haefely
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 262 Issue 3 Pg. 1121-7 (Sep 1992) ISSN: 0022-3565 [Print] United States
• PMID: 1356150 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Anxiety Agents
• Anticonvulsants
• Pyrrolidines
• Quinolizines
• Receptors, GABA-A
• Ro 19-8022
• Diazepam

Topics

• Acoustic Stimulation
• Animals
• Anti-Anxiety Agents (pharmacology)
• Anticonvulsants (pharmacology)
• Conditioning, Operant (drug effects)
• Diazepam (antagonists & inhibitors)
• Drug Evaluation, Preclinical
• Mice
• Motor Activity (drug effects)
• Pyrrolidines (pharmacology)
• Quinolizines (pharmacology)
• Rats
• Receptors, GABA-A (drug effects)
• Saimiri
• Seizures (prevention & control)
• Species Specificity