4 years ago

Towards Functional Selectivity for α6®3γ2 GABAA Receptors: A Series of Novel Pyrazoloquinolinones

Jure Fabjan, Michael Schnürch, Zdravko Varagic, Raphael Holzinger, Laurin Wimmer, David C B Siebert, Marko D Mihovilovic, Konstantina Bampali, Margot Ernst, Marco Treven, Petra Scholze, Friederike Steudle
Background and Purpose The γ - aminobutyric acid type A (GABAA) 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+/®- interfaces, using a systematically varied series of pyrazoloquinolinones. Experimental Approach Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA elicited currents by the newly synthesized and the 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 α6®3γ2 GABAA receptors with nearly no residual activity in the other αx®3γ2 (x=1-5) subtypes. This modulation was independent of affinity for α+/γ- interfaces. Furthermore, we described for the first time a compound that elicits a negative modulation at specific extracellular α+/®- interfaces. Conclusion and Implications These results constitute a major step towards a potential selective positive modulation of certain α6-containing 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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14087

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