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

GABAA 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. Experimental approach: GABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. Key

GABAA 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. Experimental approach: GABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. Key

We not only identified compounds with higher efficacy/potency than CGS 9895 for stimulating GABA-induced currents via the α1+β3-binding site, but also discovered compounds acting as null modulators at this site. Most of the compounds also acted as null modulators via the benzodiazepine binding site of GABAA receptors. But some of the positive allosteric modulators or null modulators exclusively exerted their action via the α+β- binding site.