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Design and Development of Site Specific Null Allosteric Ligands for γ‐Aminobutyric Acid Type A Receptor as Reversal Agents for General Anesthesia

The γ‐aminobutyric acid type A receptors (GABA(A)Rs) are the main inhibitory neurotransmitter receptors in the CNS. They control the synaptic and extrasynaptic GABA‐mediated inhibitory signals in the brain. They are the target of general anesthetics, sedatives and anticonvulsants. Our overall goal is to design and develop site specific Null Allosteric Ligands (NALs) for GABA(A)Rs as reversal agents of these actions. For example, faster recovery from general anesthesia is associated with less postoperative anesthesia‐related complications such as memory loss and confusion. Whereas flumazenil is a NAL that binds to the benzodiazepine site in the extracellular domain’s (ECD) α+/γ‐ interface, there are no known NALs that bind to the transmembrane domain (TMD) sites. We adopted a strategy based on the structures of etomidate, flavanols and barbiturates as starting points, while utilizing computational docking, SAR studies and radioligand binding assays to assist in the design and development of the new agents. Here, we report the first NAL that binds to the TMD of GABA(A)Rs and that antagonizes the action of R‐mTFD‐MPAB (it binds to the TMD at the α+/β− and γ+/β− interfaces), while having a marginal effect on the binding of the agonist, [3H]muscimol. The development of the first NAL(s) targeting the TMD of GABA(A)Rs will aid in understanding GABAergic actions in the CNS, support the mechanistic studies on GABA(A)Rs and potentially lead to reversal agents for general anesthesia and sedation.