SUBTYPE SELECTIVE MODULATION OF GABAA RECEPTOR BY OCINAPLON, A NOVEL COMPOUND FOR THE TREATMENT OF ANXIETY

EMMANUEL KOSTAKIS; MARIA CLARA GRAVIELLE; PHIL SKOLNICK; ARNOLD LIPPA; SHELLEY RUSSEK; DAVID FARB

Nueva Orleans

Congreso; XXXIII Reunión Anual de la Society for Neurocience; 2003

Society for Neurocience

Ocinaplon, a novel anxiolytic compound currently in phase II of clinical trials, was evaluated using binding and electrophysiological techniques for its ability to modulate the GABAA receptor mediated response.  Xenopus oocytes were used as a platform for expressing eight selected GABAA receptor combinations and assessing the ability of ocinaplon to act as a modulator of the GABA response. In the absence of the g subunit there was no apparent potentiation of the GABA-induced current. Inclusion of the g2s or g3 subunit resulted in robust potentiation of the GABA-induced current, with ocinaplon displaying both lower potencies (5 to 20 fold) and efficacies than diazepam. Although the efficacy of ocinaplon was not very different in oocytes expressing g2s or g3 subunits, the potencies of both ocinaplon and diazepam were reduced when the g2s rather than the g3 subunit was present. Competition binding experiments were performed at 0ºC using membrane homogenates of HEK cells expressing different GABAA receptor isoforms, using [3H]flumazenil as a radioligand. Whereas the potency of ocinaplon was not greatly affected by the choice of a subunit in electrophysiological studies, its binding affinity was substantially lower when a2 was present. This suggests that the choice of a subunit may influence the temperature dependence of ocinaplon binding. The results described here are consistent with the hypothesis that lower-efficacy benzodiazepine site modulators of the GABAA receptor may be able to produce anxiolysis without sedation. This research was supported by an S.R.A. from DOV Pharmaceuticals.