Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β− interface

摘要

Background and PurposeGABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular α+β− interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the α1+β3− interface of GABAA receptors.