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M.T. Iorio, K. Bampali, M. Treven, D. Siebert, M. Ernst, M.D. Mihovilovic:
"Synthesis of novel ring structures as GABAA receptor ligands with functional selectivity";
Poster: 10th Joint Meeting on Medicinal Chemistry, Dubrovnik, Croatia; 25.06.2017 - 28.06.2017; in: "10th Joint Meeting on Medicinal Chemistry", (2017), S. 124.

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 (Figure 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.