Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes

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 int...

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Autores principales:	Xenia Simeone, David C. B. Siebert, Konstantina Bampali, Zdravko Varagic, Marco Treven, Sabah Rehman, Jakob Pyszkowski, Raphael Holzinger, Friederike Steudle, Petra Scholze, Marko D. Mihovilovic, Michael Schnürch, Margot Ernst
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46343707d7194d3e987086a53ab6033f
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spelling	oai:doaj.org-article:46343707d7194d3e987086a53ab6033f2021-12-02T15:05:43ZMolecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes10.1038/s41598-017-05757-42045-2322https://doaj.org/article/46343707d7194d3e987086a53ab6033f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05757-4https://doaj.org/toc/2045-2322Abstract 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.Xenia SimeoneDavid C. B. SiebertKonstantina BampaliZdravko VaragicMarco TrevenSabah RehmanJakob PyszkowskiRaphael HolzingerFriederike SteudlePetra ScholzeMarko D. MihovilovicMichael SchnürchMargot ErnstNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xenia Simeone David C. B. Siebert Konstantina Bampali Zdravko Varagic Marco Treven Sabah Rehman Jakob Pyszkowski Raphael Holzinger Friederike Steudle Petra Scholze Marko D. Mihovilovic Michael Schnürch Margot Ernst Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
description	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.
format	article
author	Xenia Simeone David C. B. Siebert Konstantina Bampali Zdravko Varagic Marco Treven Sabah Rehman Jakob Pyszkowski Raphael Holzinger Friederike Steudle Petra Scholze Marko D. Mihovilovic Michael Schnürch Margot Ernst
author_facet	Xenia Simeone David C. B. Siebert Konstantina Bampali Zdravko Varagic Marco Treven Sabah Rehman Jakob Pyszkowski Raphael Holzinger Friederike Steudle Petra Scholze Marko D. Mihovilovic Michael Schnürch Margot Ernst
author_sort	Xenia Simeone
title	Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
title_short	Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
title_full	Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
title_fullStr	Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
title_full_unstemmed	Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
title_sort	molecular tools for gabaa receptors: high affinity ligands for β1-containing subtypes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/46343707d7194d3e987086a53ab6033f
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Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes

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