Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent

Lori-An Etherington; Balázs Mihalik; Adrienn Pálvölgyi; István Ling; Katalin Pallagi; Szabolcs Kertész; Peter Varga; Ben G. Gunn; Adam R. Brown; Matthew R. Livesey; Olivia Monteiro; Delia Belelli; József Barkóczy; Michael Spedding; István Gacsályi; Ferenc A. Antoni; Jeremy J. Lambert

doi:10.1016/j.neuropharm.2017.08.012

Selective inhibition of extra-synaptic α5-GABA_A receptors by S44819, a new therapeutic agent

Lori-An Etherington
, Balázs Mihalik
, Adrienn Pálvölgyi
, István Ling
, Katalin Pallagi
, Szabolcs Kertész
, Peter Varga
, Ben G. Gunn
, Adam R. Brown
, Matthew R. Livesey
, Olivia Monteiro
, Delia Belelli
, József Barkóczy
, Michael Spedding
, István Gacsályi
, Ferenc A. Antoni
, Jeremy J. Lambert (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

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Abstract

In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery.

Original language	English
Pages (from-to)	353-364
Number of pages	12
Journal	Neuropharmacology
Volume	125
Early online date	12 Aug 2017
DOIs	https://doi.org/10.1016/j.neuropharm.2017.08.012
Publication status	Published - Oct 2017

Keywords

Tonic inhibition
Phasic inhibition
α5-GABAA receptors
Extrasynaptic GABAA receptors
Long term potentiation
Cognition

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10.1016/j.neuropharm.2017.08.012

Author Accepted Manuscript
© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 1.86 MBLicence: CC BY-NC-ND

Lambert, Jeremy
- Neuroscience - Emeritus Professor of Neuropharmacology
Person: Honorary

Cite this

Etherington, L.-A., Mihalik, B., Pálvölgyi, A., Ling, I., Pallagi, K., Kertész, S., Varga, P., Gunn, B. G., Brown, A. R., Livesey, M. R., Monteiro, O., Belelli, D., Barkóczy, J., Spedding, M., Gacsályi, I., Antoni, F. A., & Lambert, J. J. (2017). Selective inhibition of extra-synaptic α5-GABA_A receptors by S44819, a new therapeutic agent. Neuropharmacology, 125, 353-364. https://doi.org/10.1016/j.neuropharm.2017.08.012

@article{aa52019144ca4f4b9d508834f137d030,

title = "Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent",

abstract = "In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery.",

keywords = "Tonic inhibition, Phasic inhibition, α5-GABAA receptors, Extrasynaptic GABAA receptors, Long term potentiation, Cognition",

author = "Lori-An Etherington and Bal{\'a}zs Mihalik and Adrienn P{\'a}lv{\"o}lgyi and Istv{\'a}n Ling and Katalin Pallagi and Szabolcs Kert{\'e}sz and Peter Varga and Gunn, \{Ben G.\} and Brown, \{Adam R.\} and Livesey, \{Matthew R.\} and Olivia Monteiro and Delia Belelli and J{\'o}zsef Bark{\'o}czy and Michael Spedding and Istv{\'a}n Gacs{\'a}lyi and Antoni, \{Ferenc A.\} and Lambert, \{Jeremy J.\}",

note = "Studies performed in the JJL laboratory were supported by funding from Laboratoires Servier",

year = "2017",

month = oct,

doi = "10.1016/j.neuropharm.2017.08.012",

language = "English",

volume = "125",

pages = "353--364",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Elsevier",

}

Etherington, L-A, Mihalik, B, Pálvölgyi, A, Ling, I, Pallagi, K, Kertész, S, Varga, P, Gunn, BG, Brown, AR, Livesey, MR, Monteiro, O, Belelli, D, Barkóczy, J, Spedding, M, Gacsályi, I, Antoni, FA & Lambert, JJ 2017, 'Selective inhibition of extra-synaptic α5-GABA_A receptors by S44819, a new therapeutic agent', Neuropharmacology, vol. 125, pp. 353-364. https://doi.org/10.1016/j.neuropharm.2017.08.012

TY - JOUR

T1 - Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent

AU - Etherington, Lori-An

AU - Mihalik, Balázs

AU - Pálvölgyi, Adrienn

AU - Ling, István

AU - Pallagi, Katalin

AU - Kertész, Szabolcs

AU - Varga, Peter

AU - Gunn, Ben G.

AU - Brown, Adam R.

AU - Livesey, Matthew R.

AU - Monteiro, Olivia

AU - Belelli, Delia

AU - Barkóczy, József

AU - Spedding, Michael

AU - Gacsályi, István

AU - Antoni, Ferenc A.

AU - Lambert, Jeremy J.

N1 - Studies performed in the JJL laboratory were supported by funding from Laboratoires Servier

PY - 2017/10

Y1 - 2017/10

N2 - In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery.

AB - In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery.

KW - Tonic inhibition

KW - Phasic inhibition

KW - α5-GABAA receptors

KW - Extrasynaptic GABAA receptors

KW - Long term potentiation

KW - Cognition

U2 - 10.1016/j.neuropharm.2017.08.012

DO - 10.1016/j.neuropharm.2017.08.012

M3 - Article

C2 - 28807671

SN - 0028-3908

VL - 125

SP - 353

EP - 364

JO - Neuropharmacology

JF - Neuropharmacology

ER -

Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent

Abstract

Keywords

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Lambert, Jeremy

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Selective inhibition of extra-synaptic α5-GABA_A receptors by S44819, a new therapeutic agent