Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors

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Standard

Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors. / Falk-Petersen, Christina Birkedahl; Tsonkov, Tsonko M.; Nielsen, Malene Sofie; Harpsøe, Kasper; Bundgaard, Christoffer; Frølund, Bente; Kristiansen, Uffe; Gloriam, David E.; Wellendorph, Petrine.

I: Scientific Reports, Bind 10, Nr. 1, 10078, 22.06.2020.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Falk-Petersen, CB, Tsonkov, TM, Nielsen, MS, Harpsøe, K, Bundgaard, C, Frølund, B, Kristiansen, U, Gloriam, DE & Wellendorph, P 2020, 'Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors', Scientific Reports, bind 10, nr. 1, 10078. https://doi.org/10.1038/s41598-020-66821-0

APA

Falk-Petersen, C. B., Tsonkov, T. M., Nielsen, M. S., Harpsøe, K., Bundgaard, C., Frølund, B., ... Wellendorph, P. (2020). Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors. Scientific Reports, 10(1), [10078]. https://doi.org/10.1038/s41598-020-66821-0

Vancouver

Falk-Petersen CB, Tsonkov TM, Nielsen MS, Harpsøe K, Bundgaard C, Frølund B o.a. Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors. Scientific Reports. 2020 jun 22;10(1). 10078. https://doi.org/10.1038/s41598-020-66821-0

Author

Falk-Petersen, Christina Birkedahl ; Tsonkov, Tsonko M. ; Nielsen, Malene Sofie ; Harpsøe, Kasper ; Bundgaard, Christoffer ; Frølund, Bente ; Kristiansen, Uffe ; Gloriam, David E. ; Wellendorph, Petrine. / Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors. I: Scientific Reports. 2020 ; Bind 10, Nr. 1.

Bibtex

@article{63860d8b709449d2972cfd2f0cb4a36b,
title = "Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors",
abstract = "Brain GABAΑ receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α4β1δ GABAΑ receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABAΑ receptors. The initial screening hit 2027 (IC50 of 1.03 μM) was used for analogue search resulting in 018 (IC50 of 0.088 μM). 018 was most potent at α3,4,5-subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α4β1δ receptors and displacement of [3H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABAΑ receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABAΑ receptor-mediated effects of GABA e.g. in the immune system.",
author = "Falk-Petersen, {Christina Birkedahl} and Tsonkov, {Tsonko M.} and Nielsen, {Malene Sofie} and Kasper Harps{\o}e and Christoffer Bundgaard and Bente Fr{\o}lund and Uffe Kristiansen and Gloriam, {David E.} and Petrine Wellendorph",
year = "2020",
month = "6",
day = "22",
doi = "10.1038/s41598-020-66821-0",
language = "English",
volume = "10",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors

AU - Falk-Petersen, Christina Birkedahl

AU - Tsonkov, Tsonko M.

AU - Nielsen, Malene Sofie

AU - Harpsøe, Kasper

AU - Bundgaard, Christoffer

AU - Frølund, Bente

AU - Kristiansen, Uffe

AU - Gloriam, David E.

AU - Wellendorph, Petrine

PY - 2020/6/22

Y1 - 2020/6/22

N2 - Brain GABAΑ receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α4β1δ GABAΑ receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABAΑ receptors. The initial screening hit 2027 (IC50 of 1.03 μM) was used for analogue search resulting in 018 (IC50 of 0.088 μM). 018 was most potent at α3,4,5-subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α4β1δ receptors and displacement of [3H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABAΑ receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABAΑ receptor-mediated effects of GABA e.g. in the immune system.

AB - Brain GABAΑ receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α4β1δ GABAΑ receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABAΑ receptors. The initial screening hit 2027 (IC50 of 1.03 μM) was used for analogue search resulting in 018 (IC50 of 0.088 μM). 018 was most potent at α3,4,5-subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α4β1δ receptors and displacement of [3H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABAΑ receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABAΑ receptor-mediated effects of GABA e.g. in the immune system.

U2 - 10.1038/s41598-020-66821-0

DO - 10.1038/s41598-020-66821-0

M3 - Journal article

C2 - 32572053

AN - SCOPUS:85086727118

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 10078

ER -

ID: 244048568