Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABA _A Rs

GABA_ARs are the most abundant inhibitory neuroreceptors. Drugs that enhance their action are used to treat epilepsy, anxiety, and other conditions. Benzodiazepines can exert a range of allosteric interactions from positive to negative, but they only act on γ-subunit containing GABA_ARs. Agents acting in the transmembrane domain can interact with a wider range of GABA_ARs, but they exert only positive allosteric actions, and their therapeutic actions are often limited by sedation because their binding sites are the same as those used by general anesthetics. Consequently, their therapeutic action is limited by sedation. We report the synthesis and pharmacological evaluation of several novel spiro-hydantoins that do not modulate orthosteric agonist binding but do reverse the positive allosteric action of agents acting in the transmembrane domain. The reversal action occurs in the low micromolar range and is α-subunit dependent with action on α3β3γ2 receptors occurring at concentrations as low as 200 nM.