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D. Siebert, X. Simeone, K. Bampali, Z. Varagic, M. Treven, S. Rehman, J. Pyszkowski, R. Holzinger, F. Steudle, P. Scholze, M. Schnürch, M.D. Mihovilovic, M. Ernst:
"Pyrazoloquinolinones, revisited GABAA receptor tool compounds";
Poster: 17th Blue Danube Symposium on Heterocyclic Chemistry, Linz; 30.08.2017 - 02.09.2017; in: "Book of Abstracts - 17th Blue Danube Symposium on Heterocyclic Chemistry", (2017), 151 S.

gamma - Aminobutyric acid (GABA) is a wide-spread transmitter which binds to two pharmacologically diverging GABA receptors, GABAA and GABAB. GABAA receptors (GABAARs) are transmembrane pentameric ligand-gated chloride ion channels and represent an important target of many clinically relevant drugs (e.g. benzodiazepines, barbiturates, etc.). These receptors consist of different subunits (e.g. α,β,γ, etc.), which are drawn from nineteen subunit isoforms that are grouped into classes (e.g. α1-α6, β1- β3, etc.).[1-4] The pyrazoloquinolinone (PQ) ligands bind at the benzodiazepine (BZ) binding site (α+/γ- interface) and at the newly described α+/β- interface.[5] This compound class has proven to be a valuable tool to investigate the GABAAR function.
Here, a small set of pyrazoloquinolinones were synthesized which show the following properties: high affinity to the BZ binding site and low-potency modulation at the α+/β- interface. In addition we report the first β - subtype selective compounds that even distinguish between all three beta isoforms. These findings provide more insights into the subtype-selective modulation of GABAARs. Further investigation could not only result in beneficial pharmacological tools, but also in selective ligands for receptor pools that cannot be targeted with existing compounds.