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Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones

BACKGROUND AND PURPOSE: The GABA(A) 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 speci...

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Autores principales: Treven, Marco, Siebert, David C B, Holzinger, Raphael, Bampali, Konstantina, Fabjan, Jure, Varagic, Zdravko, Wimmer, Laurin, Steudle, Friederike, Scholze, Petra, Schnürch, Michael, Mihovilovic, Marko D, Ernst, Margot
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773961/
https://www.ncbi.nlm.nih.gov/pubmed/29127702
http://dx.doi.org/10.1111/bph.14087
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author Treven, Marco
Siebert, David C B
Holzinger, Raphael
Bampali, Konstantina
Fabjan, Jure
Varagic, Zdravko
Wimmer, Laurin
Steudle, Friederike
Scholze, Petra
Schnürch, Michael
Mihovilovic, Marko D
Ernst, Margot
author_facet Treven, Marco
Siebert, David C B
Holzinger, Raphael
Bampali, Konstantina
Fabjan, Jure
Varagic, Zdravko
Wimmer, Laurin
Steudle, Friederike
Scholze, Petra
Schnürch, Michael
Mihovilovic, Marko D
Ernst, Margot
author_sort Treven, Marco
collection PubMed
description BACKGROUND AND PURPOSE: The GABA(A) 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 GABA(A) 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 GABA(A) 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 GABA(A) 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 GABA(A) receptor isoforms.
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spelling pubmed-57739612018-01-31 Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones Treven, Marco Siebert, David C B Holzinger, Raphael Bampali, Konstantina Fabjan, Jure Varagic, Zdravko Wimmer, Laurin Steudle, Friederike Scholze, Petra Schnürch, Michael Mihovilovic, Marko D Ernst, Margot Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The GABA(A) 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 GABA(A) 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 GABA(A) 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 GABA(A) 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 GABA(A) receptor isoforms. John Wiley and Sons Inc. 2017-12-22 2018-02 /pmc/articles/PMC5773961/ /pubmed/29127702 http://dx.doi.org/10.1111/bph.14087 Text en © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research Papers
Treven, Marco
Siebert, David C B
Holzinger, Raphael
Bampali, Konstantina
Fabjan, Jure
Varagic, Zdravko
Wimmer, Laurin
Steudle, Friederike
Scholze, Petra
Schnürch, Michael
Mihovilovic, Marko D
Ernst, Margot
Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title_full Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title_fullStr Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title_full_unstemmed Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title_short Towards functional selectivity for α6β3γ2 GABA(A) receptors: a series of novel pyrazoloquinolinones
title_sort towards functional selectivity for α6β3γ2 gaba(a) receptors: a series of novel pyrazoloquinolinones
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773961/
https://www.ncbi.nlm.nih.gov/pubmed/29127702
http://dx.doi.org/10.1111/bph.14087
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