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D. Siebert:
"Auf dem Weg zu selektiven Liganden für das GABAA Rezeptor alpha+/beta- Interface";
Betreuer/in(nen), Begutachter/in(nen): M. Schnürch, M. Ernst; Institut für Angewandte Synthesechemie, 2018; Rigorosum: 23.02.2018.

The neurotransmitter gamma- aminobutyric acid (GABA) occurs ubiquitously in our central nervous system (CNS) and binds, inter alia, to a class of ligand-gated ion channels called GABAA receptors. These pentameric receptors are targets of many clinically relevant drugs (e.g. benzodiazepines). The family contains many different subunits which are further classified into isoforms (e.g. alpha1-6, beta1-3, gamma1-3, etc). Thus, there exists an enormous number of possible different subunit assemblies (receptor subtypes) which results in a very complex pharmacology of these receptors. Hence, the exploration of selective pharmacological tool compounds to study GABAA receptors is of great importance. The compound class of pyrazoloquinolinones (PQs) is known to interact with the high affinity alpha+/gamma2- interface (benzodiazepine binding site) and the low affinity modulatory site at the alpha+/beta- interface. Therefore, PQs represent a suitable starting point to study the molecular determinants which influence the mechanism of allosteric modulation at the two homologous binding sites. In this thesis we synthesized a systematic library of differently substituted PQs and were able to identify two subtype selective prototypes which served as proof of concept in the development of urgently required subtype selective tool compounds. Moreover, we elucidated the binding mode of PQs at the alpha1+/gamma2- site by establishing a novel docking protocol which assesses SAR data during the scoring process. The combination of these findings led to innovative ligand designs which should exclusively interact with the alpha+/beta- interfaces and will be investigated in future studies.

https://publik.tuwien.ac.at/files/publik_277588.pdf