[Zurück]

M. Treven, D. Siebert, R. Holzinger, K. Bampali, J. Fabjan, Z. Varagic, L. Wimmer, F. Steudle, P. Scholze, M. Schnürch, M.D. Mihovilovic, M. Ernst:
"Towards functional selectivity for α6β3γ2 GABAA receptors: a series of novel pyrazoloquinolinones";
British Journal of Clinical Pharmacology, (*) (2017), (*).

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

http://dx.doi.org/10.1111/bph.14087