Abstract
Benzodiazepines are an important class of psychiatric medicines used widely for the treatment of anxiety and sleep disorders, but clinical use is limited by their significant liability for addiction and physical dependence. We identified a compound with a promising pharmacological profile for treating benzodiazepine addiction: The imidazotriazine TPA023B, which has no intrinsic efficacy (i.e., is a silent allosteric modulator) at α1-subunit containing GABA(A) receptors (α1GABA(A) receptors), but has partial positive modulatory activity at α2GABA(A), α3GABA(A) and α5GABA(A) receptors. TPA023B previously showed only limited addiction liability compared to available addictive benzodiazepines. In the present study, TPA023B dose-dependently blocked self-administration of the conventional benzodiazepine, midazolam, in rhesus monkeys but had no effects on food self-administration in these same subjects. Importantly, TPA023B had anxiolytic-like effects in monkeys at the same doses that blocked benzodiazepine self-administration, which were estimated to result in 70-80% receptor occupancy (levels shown to be achievable in human patients). In acute dependence models, TPA023B did not precipitate withdrawal-like effects after diazepam administration in rats or midazolam administration in rhesus monkeys. Most strikingly, TPA023B reversed the withdrawal-like effects precipitated by the benzodiazepine silent allosteric modulator flumazenil in monkeys. Because TPA023B has been administered successfully to human subjects in clinical trials, our preclinical data support the development of TPA023B as the first maintenance pharmacotherapy for patients misusing benzodiazepines, having a use disorder involving a benzodiazepine, and/or having physical dependence.