Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin

Research output: Contribution to journalJournal articleResearchpeer-review

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Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin. / Eghorn, Laura Friis; Høstgaard-Jensen, Kirsten; Kongstad, Kenneth Thermann; Bay, Tina; Higgins, David; Frølund, Bente; Wellendorph, Petrine.

In: European Journal of Pharmacology, Vol. 740, 05.10.2014, p. 570-577.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Eghorn, LF, Høstgaard-Jensen, K, Kongstad, KT, Bay, T, Higgins, D, Frølund, B & Wellendorph, P 2014, 'Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin', European Journal of Pharmacology, vol. 740, pp. 570-577. https://doi.org/10.1016/j.ejphar.2014.06.028

APA

Eghorn, L. F., Høstgaard-Jensen, K., Kongstad, K. T., Bay, T., Higgins, D., Frølund, B., & Wellendorph, P. (2014). Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin. European Journal of Pharmacology, 740, 570-577. https://doi.org/10.1016/j.ejphar.2014.06.028

Vancouver

Eghorn LF, Høstgaard-Jensen K, Kongstad KT, Bay T, Higgins D, Frølund B et al. Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin. European Journal of Pharmacology. 2014 Oct 5;740:570-577. https://doi.org/10.1016/j.ejphar.2014.06.028

Author

Eghorn, Laura Friis ; Høstgaard-Jensen, Kirsten ; Kongstad, Kenneth Thermann ; Bay, Tina ; Higgins, David ; Frølund, Bente ; Wellendorph, Petrine. / Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin. In: European Journal of Pharmacology. 2014 ; Vol. 740. pp. 570-577.

Bibtex

@article{2706355a346a4dec9a128a5b13a03391,
title = "Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin",
abstract = "γ-Hydroxybutyric acid (GHB) is a metabolite of γ-aminobutyric acid (GABA) and a proposed neurotransmitter in the mammalian brain. We recently identified α4βδ GABAA receptors as possible high-affinity GHB targets. GABAA receptors are highly sensitive to allosteric modulation. Thus to investigate whether GHB high-affinity binding sites are also sensitive to allosteric modulation, we screened both known GABAA receptor ligands and a library of natural compounds in the rat cortical membrane GHB specific high-affinity [3H]NCS-382 binding assay. Two hits were identified: Monastrol, a positive allosteric modulator of GABA function at δ-containing GABAA receptors, and the naturally occurring flavonoid catechin. These compounds increased [3H]NCS-382 binding to 185-272{\%} in high micromolar concentrations. Monastrol and (+)-catechin significantly reduced [3H]NCS-382 dissociation rates and induced conformational changes in the binding site, demonstrating a positive allosteric modulation of radioligand binding. Surprisingly, binding of [3H]GHB and the GHB high-affinity site-specific radioligands [125I]BnOPh-GHB and [3H]HOCPCA was either decreased or only weakly increased, indicating that the observed modulation was critically probe-dependent. Both monastrol and (+)-catechin were agonists at recombinant α4β3δ receptors expressed in Xenopus laevis oocytes. When monastrol and GHB were co-applied no changes were seen compared to the individual responses. In summary, we have identified the compounds monastrol and catechin as the first allosteric modulators of GHB high-affinity binding sites. Despite their relatively weak affinity, these compounds may aid in further characterization of the GHB high-affinity sites that are likely to represent certain GABAA receptors.",
keywords = "γ-Hydroxybutyric acid, Dihydropyrimidinone, Flavonoid, GHB receptor, NCS-382, Probe dependence",
author = "Eghorn, {Laura Friis} and Kirsten H{\o}stgaard-Jensen and Kongstad, {Kenneth Thermann} and Tina Bay and David Higgins and Bente Fr{\o}lund and Petrine Wellendorph",
year = "2014",
month = "10",
day = "5",
doi = "10.1016/j.ejphar.2014.06.028",
language = "English",
volume = "740",
pages = "570--577",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Positive allosteric modulation of the GHB high-affinity binding site by the GABAA receptor modulator monastrol and the flavonoid catechin

AU - Eghorn, Laura Friis

AU - Høstgaard-Jensen, Kirsten

AU - Kongstad, Kenneth Thermann

AU - Bay, Tina

AU - Higgins, David

AU - Frølund, Bente

AU - Wellendorph, Petrine

PY - 2014/10/5

Y1 - 2014/10/5

N2 - γ-Hydroxybutyric acid (GHB) is a metabolite of γ-aminobutyric acid (GABA) and a proposed neurotransmitter in the mammalian brain. We recently identified α4βδ GABAA receptors as possible high-affinity GHB targets. GABAA receptors are highly sensitive to allosteric modulation. Thus to investigate whether GHB high-affinity binding sites are also sensitive to allosteric modulation, we screened both known GABAA receptor ligands and a library of natural compounds in the rat cortical membrane GHB specific high-affinity [3H]NCS-382 binding assay. Two hits were identified: Monastrol, a positive allosteric modulator of GABA function at δ-containing GABAA receptors, and the naturally occurring flavonoid catechin. These compounds increased [3H]NCS-382 binding to 185-272% in high micromolar concentrations. Monastrol and (+)-catechin significantly reduced [3H]NCS-382 dissociation rates and induced conformational changes in the binding site, demonstrating a positive allosteric modulation of radioligand binding. Surprisingly, binding of [3H]GHB and the GHB high-affinity site-specific radioligands [125I]BnOPh-GHB and [3H]HOCPCA was either decreased or only weakly increased, indicating that the observed modulation was critically probe-dependent. Both monastrol and (+)-catechin were agonists at recombinant α4β3δ receptors expressed in Xenopus laevis oocytes. When monastrol and GHB were co-applied no changes were seen compared to the individual responses. In summary, we have identified the compounds monastrol and catechin as the first allosteric modulators of GHB high-affinity binding sites. Despite their relatively weak affinity, these compounds may aid in further characterization of the GHB high-affinity sites that are likely to represent certain GABAA receptors.

AB - γ-Hydroxybutyric acid (GHB) is a metabolite of γ-aminobutyric acid (GABA) and a proposed neurotransmitter in the mammalian brain. We recently identified α4βδ GABAA receptors as possible high-affinity GHB targets. GABAA receptors are highly sensitive to allosteric modulation. Thus to investigate whether GHB high-affinity binding sites are also sensitive to allosteric modulation, we screened both known GABAA receptor ligands and a library of natural compounds in the rat cortical membrane GHB specific high-affinity [3H]NCS-382 binding assay. Two hits were identified: Monastrol, a positive allosteric modulator of GABA function at δ-containing GABAA receptors, and the naturally occurring flavonoid catechin. These compounds increased [3H]NCS-382 binding to 185-272% in high micromolar concentrations. Monastrol and (+)-catechin significantly reduced [3H]NCS-382 dissociation rates and induced conformational changes in the binding site, demonstrating a positive allosteric modulation of radioligand binding. Surprisingly, binding of [3H]GHB and the GHB high-affinity site-specific radioligands [125I]BnOPh-GHB and [3H]HOCPCA was either decreased or only weakly increased, indicating that the observed modulation was critically probe-dependent. Both monastrol and (+)-catechin were agonists at recombinant α4β3δ receptors expressed in Xenopus laevis oocytes. When monastrol and GHB were co-applied no changes were seen compared to the individual responses. In summary, we have identified the compounds monastrol and catechin as the first allosteric modulators of GHB high-affinity binding sites. Despite their relatively weak affinity, these compounds may aid in further characterization of the GHB high-affinity sites that are likely to represent certain GABAA receptors.

KW - γ-Hydroxybutyric acid

KW - Dihydropyrimidinone

KW - Flavonoid

KW - GHB receptor

KW - NCS-382

KW - Probe dependence

U2 - 10.1016/j.ejphar.2014.06.028

DO - 10.1016/j.ejphar.2014.06.028

M3 - Journal article

VL - 740

SP - 570

EP - 577

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -

ID: 127925270