Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones

The GABA_A receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/β- interfaces, using a systematically varied series of pyrazoloquinolinones.

Recombinant GABA_A receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA-elicited currents by the newly synthesized and reference compounds were investigated by the two-electrode voltage clamp method.

We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6β3γ2 GABA_A receptors with nearly no residual activity at the other αxβ3γ2 (x = 1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/β- interfaces.

These results constitute a major step towards a potential selective positive modulation of certain α6-containing GABA_A receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABA_A receptor isoforms.