Abstract
GABA(A)Rs are pentameric ligand-gated ion channels that play a major role in mediating inhibition in the CNS. They are the target of many widely used positive allosteric modulators (PAMs) of GABA(A)Rs such as general anesthetics, sedatives, antiepileptics, and anxiolytics. However, close structural analogs of these PAMs are negative allosteric modulators that cause excitation. Comparison of the SAR of inhibitory and excitatory barbiturates suggested that conformationally constrained spiro-analogs of phenobarbital might have intermediate allosteric activity. More than 50 spiro-analogs were synthesized and characterized for their ability to enhance desensitization and reverse the action of anesthetics. A number of these reversed the action of anesthetics without having any action on GABA-induced desensitization. These constitute a new class of GABA-ergic drugs that are null allosteric ligands. They offer the potential to reverse the sedative action of current PAMs and modulate the behavior of diseases resulting from mutations in GABA(A)R subunits.