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

摘要: Background and purpose The GABAA receptors are ligand-gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as appealing target for many clinically relevant drugs. Here, we explored the functional selectivity modulatory effects at specific extracellular α+/β- interfaces, using a systematically varied series pyrazoloquinolinones. Experimental approach Recombinant were expressed Xenopus laevis oocytes on GABA-elicited currents by newly synthesized reference compounds investigated two-electrode voltage clamp method. Key results We identified new compound which, to best our knowledge, shows highest positive modulation α6β3γ2 with nearly no residual activity other αxβ3γ2 (x = 1-5) subtypes. This was independent affinity α+/γ- interfaces. Furthermore, demonstrated first time that elicits negative Conclusion implications These constitute major step towards potential selective certain α6-containing receptors, might be useful elicit their physiological role. these studies pave way insights into molecular principles drive versus allosteric receptor isoforms.