Abstract
GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in α1β2γ2 GABAA receptors using an experiment-guided virtual screening (EGVS) method. This screen also identified novel ligands for intramembrane low affinity diazepam site(s). In the current study we have further characterized compounds 31 and 132 identified with EGVS as well as 4-O-methylhonokiol. We investigated the site of action of these compounds in α1β2γ2 GABAA receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology combined with a benzodiazepine site antagonist and transmembrane domain mutations. All three compounds act mainly through the two β+/α− subunit transmembrane interfaces of the GABAA receptors. We then used concatenated receptors to dissect the involvement of individual β+/α− interfaces. We further demonstrated that these compounds have anesthetic activity in a small aquatic animal model, Xenopus laevis tadpoles. The newly identified compounds may serve as scaffolds for the development of novel anesthetics.
Highlights
GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics
In an attempt to find novel ligands for the high affinity site for benzodiazepines on GABAA receptors we screened 198 compounds for displacement of the high affinity benzodiazepine site antagonist [3H]-Ro 15-1788 at receptors expressed in HEK-cells
The above data suggests that the modulatory site(s) for the three compounds we studied is located in one or both of the β+/α−transmembrane domain (TMD) subunit interfaces on α1β2γ2 GABAA receptors
Summary
GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in α1β2γ2 GABAA receptors using an experiment-guided virtual screening (EGVS) method. This screen identified novel ligands for intramembrane low affinity diazepam site(s). A key site of action of the potent anesthetics propofol and etomidate is the major inhibitory receptor in the mammalian central nervous system, the γ-aminobutyric acid type A (GABAA) receptor. These receptors are composed of five homologous subunits organized around a central Cl− selective channel[3].
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