[Zurück]

X. Simeone, D. Siebert, K. Bampali, Z. Varagic, M. Treven, S. Rehman, J. Pyszkowski, R. Holzinger, F. Steudle, P. Scholze, M.D. Mihovilovic, M. Schnürch, M. Ernst:
"Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes";
Scientific Reports, 7 (2017), 5674.

γ-Aminobutyric acid type A (GABAA) receptors are pentameric GABA-gated chloride channels that
are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π
and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different
subunit compositions result in miscellaneous receptor subtypes. In combination with the large number
of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently,
a novel binding site at extracellular α+/β− interfaces was described as the site of modulatory action
of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of
compounds with pronounced β1-selectivity that mainly lacks α-subunit selectivity. It constitutes the
most potent β1-selective positive allosteric modulatory ligand with known binding site. In addition, a
proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the
benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular
tools for the detection of β1-containing receptor subtypes and the investigation of their abundance and
distribution.

http://dx.doi.org/10.1038/s41598-017-05757-4