Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic.
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.
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
F
F
Jenck
J L
JL
Moreau
E P
EP
Bonetti
J R
JR
Martin
W E
WE
Haefely
D000161:Acoustic Stimulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003975:Diazepam / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D011807:Quinolizines / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D012453:Saimiri; D012640:Seizures / Q000517:prevention & control; D013045:Species Specificity
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011759:Pyrrolidines; D011807:Quinolizines; D011963:Receptors, GABA-A; C076809:Ro 19-8022; D003975:Diazepam