Towards functional selectivity for 632 GABAA receptors: a series of novel pyrazoloquinolinones

Background and Purpose The GABAA receptors are ligandgated 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 +/ interfaces, using a systematically varied series of pyrazoloquinolinones. Experimental Approach Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABAelicited currents by the newly synthesized and reference compounds were investigated by the twoelectrode 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 632 GABAA receptors with nearly no residual activity at the other x32 (x = 15) subtypes. This modulation was independent of affinity for +/ interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular +/ interfaces. Conclusion and Implications These results constitute a major step towards a potential selective positive modulation of certain 6containing GABAA 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 GABAA receptor isoforms.(VLID)480595