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 (Lead / Corresponding author)

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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 languageEnglish
    Pages (from-to)353-364
    Number of pages12
    JournalNeuropharmacology
    Volume125
    Early online date12 Aug 2017
    DOIs
    Publication statusPublished - Oct 2017

    Fingerprint

    GABA-A Receptors
    Benzodiazepines
    gamma-Aminobutyric Acid
    Therapeutics
    Central Nervous System
    GABA-A Receptor Agonists
    Neurons
    Flumazenil
    Muscimol
    Neurotransmitter Receptor
    Neuronal Plasticity
    Scopolamine Hydrobromide
    Long-Term Potentiation
    HEK293 Cells
    Inhibition (Psychology)
    Short-Term Memory
    Neurodegenerative Diseases
    Cognition
    Protein Isoforms
    Stroke

    Keywords

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

    Cite this

    Etherington, Lori-An ; Mihalik, Balázs ; Pálvölgyi, Adrienn ; Ling, István ; Pallagi, Katalin ; Kertész, Szabolcs ; Varga, Peter ; Gunn, Ben G. ; Brown, Adam R. ; Livesey, Matthew R. ; Monteiro, Olivia ; Belelli, Delia ; Barkóczy, József ; Spedding, Michael ; Gacsályi, István ; Antoni, Ferenc A. ; Lambert, Jeremy J. / Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent. In: Neuropharmacology. 2017 ; Vol. 125. pp. 353-364.
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    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.",
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    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.}",
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    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-GABAA receptors by S44819, a new therapeutic agent', Neuropharmacology, vol. 125, pp. 353-364. https://doi.org/10.1016/j.neuropharm.2017.08.012

    Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent. / Etherington, Lori-An; Mihalik, Balázs; Pálvölgyi, Adrienn; Ling, István; Pallagi, Katalin; Kertész, Szabolcs; Varga, Peter; Gunn, Ben G.; Brown, Adam R.; Livesey, Matthew R.; Monteiro, Olivia; Belelli, Delia; Barkóczy, József; Spedding, Michael; Gacsályi, István; Antoni, Ferenc A.; Lambert, Jeremy J. (Lead / Corresponding author).

    In: Neuropharmacology, Vol. 125, 10.2017, p. 353-364.

    Research output: Contribution to journalArticle

    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

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    Etherington L-A, Mihalik B, Pálvölgyi A, Ling I, Pallagi K, Kertész S et al. Selective inhibition of extra-synaptic α5-GABAA receptors by S44819, a new therapeutic agent. Neuropharmacology. 2017 Oct;125:353-364. https://doi.org/10.1016/j.neuropharm.2017.08.012