Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator

Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therap...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-05, Vol.102 (20), p.7380-7385
Main Authors: Lippa, A, Czobor, P, Stark, J, Beer, B, Kostakis, E, Gravielle, M, Bandyopadhyay, S, Russek, S J, Gibbs, T T, Farb, D H, Skolnick, P
Format: Article
Language:English
Subjects:
Adult
Animals
Anti-Anxiety Agents - adverse effects
Anti-Anxiety Agents - pharmacology
Anti-Anxiety Agents - therapeutic use
Anticonvulsants - pharmacology
Anxiety Disorders - drug therapy
Anxiety Disorders - metabolism
Behavior, Animal - drug effects
Conditioning, Operant
Diazepam - pharmacology
Double-Blind Method
Flunitrazepam - metabolism
Germany
Humans
Oocytes - metabolism
Patch-Clamp Techniques
Pentylenetetrazole
Pyrimidines - adverse effects
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Rats
Receptors, GABA-A - metabolism
Saimiri
Tritium
Xenopus laevis
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Summary:Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg/kg) in the Vogel "conflict" test. This anticonflict effect is blocked by flumazenil (Ro 15-1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABA(A) receptors. Nonetheless, in eight recombinant GABA(A) receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180-240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0502579102