Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABAARs

GABAARs are members of the Cys–loop pentameric ligand-gated ion channel superfamily of receptors and are the most abundant inhibitory receptors in the CNS. Drugs that enhance the action of GABAARs are used to treat epilepsy, anxiety and other conditions but their therapeutic action is often limited by sedation because their binding sites are the same as those used by sedatives and general anesthetics. With the exception of the benzodiazepines, which only act on synaptic GABAARs that contain one γ-subunit, little progress has been made on this problem. Recently, it was shown that certain spiro-barbiturates can reverse the action of anesthetics on both synaptic and extrasynaptic GABAARs. However, barbiturates interact with other members of the Cys–loop pentameric ligand-gated ion channel superfamily. In this work, we report the synthesis and pharmacological evaluation of novel spiro-hydantoins, none of which are positive allosteric modulators. They retain the property of the spiro-barbiturates to reverse the action of anesthetics and some of them do so with higher affinity and efficacy than achieved with spirobarbiturates. Furthermore, the reversal action on α3β3γ2 receptors occurs in the submicromolar range, which represents a 200-fold selectivity over α1β3γ2 receptors. As such, spiro hydantoins offer a promising new platform for development.