Abstract
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.
Highlights
Xenia Simeone[1], David C
As we have described previously, many R8 and R′4 di-substituted pyrazoloquinolinones interact with the α+/β− interfaces, and bind with very high affinity to α+/γ2− interfaces[22, 23, 26]
Since many R8 and R′4 substituted pyrazoloquinolinones interact with the α+/β− interfaces, but are very high affinity ligands at αk+/γ2- interfaces[22, 23, 26], we examined the affinity of our six test ligands for the α1+/γ2- site with flunitrazepam displacement assays using cerebellar membrane preparations from rat brains
Summary
Xenia Simeone[1], David C. Mihovilovic[2], Michael Schnürch2 & Margot Ernst 1 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 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. A proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented 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.
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