Anxiety - ocinaplon
GABA, or γ-aminobutyric acid, is the main inhibitory neurotransmitter within the central nervous system in mammals, where it has a wide variety of psychological and physiological functions. GABAA receptors are made up of a hetero-oligomeric protein complex, with a GABA binding site attached to an integral chloride ion channel. Many different GABAA receptor subtypes have been identified. The diversity of receptor subtypes means there is the potential for creating very specific drug treatments that are precisely targeted.
GABAA receptors are implicated in both the physical and behavioural symptoms of anxiety, making them attractive targets for anxiolytic medicines, as well as sedatives and anticonvulsants. Benzodiazepines, still the most important class of medicines used to treat anxiety, enhance the binding of GABA at the endogenous receptor sites, increasing the conductance of chloride ions through the GABAA receptor coupled channel. However, the benzodiazepines have a range of side effects that limit their usefulness, such as tolerance, sedation, amnesia and the potential for abuse.
The anxiolytic and sedative effects of the benzodiazepines have been shown to be mediated by the α2 and α1 GABAA receptor subtypes, so a drug that acts selectively at the right receptor subtype could have huge potential as an anxiolytic medicine.
Ocinaplon is a drug with this action that was initially discovered by Wyeth, and has been licensed to Elan and DOV Pharmaceutical.1 A total of seven placebo-controlled double-blind Phase I studies in more than 140 healthy volunteers have been carried out with ocinaplon.2 It was found to be well tolerated, with no evidence of sedative or muscular side effects. In a Phase II randomised double-blind placebo-controlled trial, 60 patients with generalised anxiety disorder were given 90mg/kg ocinaplon three times a day or placebo for four weeks. Significant decreases in several anxiety measures were seen during the period of treatment, with some reductions being seen after just one week of treatment, showing it has a much faster onset of action than traditional anxiolytics.
Another Phase II trial looked at the efficacy of a controlled release formulation of the drug in 117 patients, who received 120mg twice a day or 60mg three times a day for 14 days.2 It caused a significant reduction in measures of anxiety in those given the active, and was well tolerated, with a reduced tendency for physical dependence. Rebound anxiety after treatment was stopped was not seen either.