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.