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

BACKGROUND AND PURPOSE 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 alpha+/beta- interfaces, using a systematically varied series of pyrazoloquinolinones. EXPERIMENTAL APPROACH 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. KEY RESULTS We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at alpha 6 beta 3 gamma 2 GABA(A) receptors with nearly no residual activity at the other alpha x beta 3 gamma 2 (x = 1-5) subtypes. This modulation was independent of affinity for alpha+/beta- interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular alpha+/beta- interfaces. CONCLUSION AND IMPLICATIONS These results constitute a major step towards a potential selective positive modulation of certain alpha 6-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.