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A NOVEL PYRAZOLOQUINOLINONE RADIOLIGAND WITH A UNIQUE GABA<SUB >A</SUB> RECEPTOR SELECTIVITY PROFILE
Petra Scholzeand 7 co-authors
Medical University of Vienna
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS01-07AM-025
Presentation
Date TBA
Board: PS01-07AM-025
Event Information
Poster Board
PS01-07AM-025
Poster
View posterAbstract
GABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain, exist as different receptor subtypes and are the target of many clinically important drugs. The present GABAergic drugs, however, display very little selectivity, and side effects might be limited if more specific drugs could be identified.
The most prominent receptor subtype is αxβxγ2. GABA binds at the extracellular β+α- region, while benzodiazepines interact with the α+γ- interface. In a previous study1 using oocyte electrophysiology pyrazoloquinolinone ligands could be identified that bind to the so far little investigated α+β- interface. One of those compounds showed to be a potent β1-selective positive allosteric modulator2.
In the present study, this compound was synthesized as a tritium-labeled radioligand and subsequently evaluated in radioligand binding assays employing heterologously expressed GABAA receptors in transfected HEK293 cells and native rat brain tissue.
Our studies show that this novel radioligand binds specifically to α1β1 receptors, and not to α1β2/3 in the high nM range, consistent with the published electrophysiology2. This binding can be dose-dependently displaced by other pyrazoloquinolinones with similar structure, and reduced with an extracellular conversion mutant. This radioligand can now be used to further investigate β1- containing GABAA receptors.
1 Varagic, Z. et al. (2013) Br J Pharmacol 169, 371–383.
2 Simeone, X. et al. (2017) Sci Rep 7, 5674.
This research was funded by the Austrian Science Fund (FWF) grant W1232.
The most prominent receptor subtype is αxβxγ2. GABA binds at the extracellular β+α- region, while benzodiazepines interact with the α+γ- interface. In a previous study1 using oocyte electrophysiology pyrazoloquinolinone ligands could be identified that bind to the so far little investigated α+β- interface. One of those compounds showed to be a potent β1-selective positive allosteric modulator2.
In the present study, this compound was synthesized as a tritium-labeled radioligand and subsequently evaluated in radioligand binding assays employing heterologously expressed GABAA receptors in transfected HEK293 cells and native rat brain tissue.
Our studies show that this novel radioligand binds specifically to α1β1 receptors, and not to α1β2/3 in the high nM range, consistent with the published electrophysiology2. This binding can be dose-dependently displaced by other pyrazoloquinolinones with similar structure, and reduced with an extracellular conversion mutant. This radioligand can now be used to further investigate β1- containing GABAA receptors.
1 Varagic, Z. et al. (2013) Br J Pharmacol 169, 371–383.
2 Simeone, X. et al. (2017) Sci Rep 7, 5674.
This research was funded by the Austrian Science Fund (FWF) grant W1232.
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