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M.T. Iorio, L. Wimmer, K. Bampali, M. Ernst, M.D. Mihovilovic:
"Synthesis of novel ring structures as GABAA receptor ligands with functional selectivity";
Poster: 17th Blue Danube Symposium on Heterocyclic Chemistry, Linz; 30.08.2017 - 02.09.2017; in: "17th blue danube symposium on heterocyclic chemistry", (2017), S. 83.

The GABAA receptors are pentameric channel proteins with an high subunit diversity. So far 19
subunits were identified: six α subunit, three β, three γ, one δ, one ε, one θ, one π and three ρ
subunits. The different subunits can be combined in different ways to for
the pentamer, but the most accepted structure presents two α-, two β- and
one γ- subunits. [1] Upon the binding of two molecules of GABA to the
receptor, the pore opens and allows the influx of chloride ions. While the
benzodiazepines act as positive allosteric modulator via a binding site
located at the α+γ- interface in the extracellular domain of GABAA
receptors, the 2 GABA binding sites are located at the two β+α-.[2]
The GABAA receptor is the target of many clinically relevant drugs such
as benzodiazepine, barbiturates and steroids for the treatment of anxiety,
depression and epilepsy. Eventhough, benzodiazepines are excellent anxiolytic drugs, they show
sedative side effects and due to their addictive properties they cannot be used in long term
treatment. For this reason and in order to develop tools for further studies of the GABAA receptor
new compounds need to be investigated.
Pyrazoloquinolinones were found to act as positive modulators at the α+β- interface,
maintaining a high affinity for the benzodiazepine binding site of the receptor.
In order to gain selectivity for the binding site at the α+β- interface some modifications of
this scaffold are required. Therefore, a more stretched structure needs to be synthesized
which may interact better with the β subunit of the receptor, giving as a result a loss in
affinity for the binding site at the α+γ- interface. [3]
For this purpose a series of indoles derivatives was synthesized (Fig. 3). These compounds
might maintain the same binding mode at the desired interface due to the analogy with the
closed structure. Some preliminary results showed that compounds like these have low
affinity for the benzodiazepine binding site, maintaining the modulation of the GABA
induced current in receptor containing α and β subunits. Due to their interesting properties
these compounds will be further investigated.