Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites. / Krall, Jacob; Bavo, Francesco; Falk-Petersen, Christina B; Jensen, Claus Hatt; Nielsen, Julie Olsson; Tian, Yongsong; Anglani, Valeria; Kongstad, Kenneth Thermann; Piilgaard, Louise; Nielsen, Birgitte; Gloriam, David E; Kehler, Jan; Jensen, Anders A.; Harpsøe, Kasper; Wellendorph, Petrine; Frølund, Bente.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2798-2813.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Krall, J, Bavo, F, Falk-Petersen, CB, Jensen, CH, Nielsen, JO, Tian, Y, Anglani, V, Kongstad, KT, Piilgaard, L, Nielsen, B, Gloriam, DE, Kehler, J, Jensen, AA, Harpsøe, K, Wellendorph, P & Frølund, B 2019, 'Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites', Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2798-2813. https://doi.org/10.1021/acs.jmedchem.9b00131

APA

Krall, J., Bavo, F., Falk-Petersen, C. B., Jensen, C. H., Nielsen, J. O., Tian, Y., Anglani, V., Kongstad, K. T., Piilgaard, L., Nielsen, B., Gloriam, D. E., Kehler, J., Jensen, A. A., Harpsøe, K., Wellendorph, P., & Frølund, B. (2019). Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites. Journal of Medicinal Chemistry, 62(5), 2798-2813. https://doi.org/10.1021/acs.jmedchem.9b00131

Vancouver

Krall J, Bavo F, Falk-Petersen CB, Jensen CH, Nielsen JO, Tian Y et al. Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites. Journal of Medicinal Chemistry. 2019 Mar 14;62(5):2798-2813. https://doi.org/10.1021/acs.jmedchem.9b00131

Author

Krall, Jacob ; Bavo, Francesco ; Falk-Petersen, Christina B ; Jensen, Claus Hatt ; Nielsen, Julie Olsson ; Tian, Yongsong ; Anglani, Valeria ; Kongstad, Kenneth Thermann ; Piilgaard, Louise ; Nielsen, Birgitte ; Gloriam, David E ; Kehler, Jan ; Jensen, Anders A. ; Harpsøe, Kasper ; Wellendorph, Petrine ; Frølund, Bente. / Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2798-2813.

Bibtex

@article{93628df26b0542feae248d0e705b87a1,
title = "Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites",
abstract = "Gabazine, a GABAA receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance GHB. We herein report a study on the structural determinants of gabazine for binding to i) the orthosteric binding site of the GABAA receptor and ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogs with relatively high affinity (Ki 0.19-2.19 µM) and >50 times selectivity for the [3H]NCS-382 over [3H]muscimol binding sites. These results highlight that gabazine interacts with the high-affinity GHB and orthosteric GABAA receptor binding sites differently, and that distinct analogs can be generated to select between them. To facilitate further in vivo studies a promising prodrug candidate for brain delivery was identified.",
author = "Jacob Krall and Francesco Bavo and Falk-Petersen, {Christina B} and Jensen, {Claus Hatt} and Nielsen, {Julie Olsson} and Yongsong Tian and Valeria Anglani and Kongstad, {Kenneth Thermann} and Louise Piilgaard and Birgitte Nielsen and Gloriam, {David E} and Jan Kehler and Jensen, {Anders A.} and Kasper Harps{\o}e and Petrine Wellendorph and Bente Fr{\o}lund",
year = "2019",
month = mar,
day = "14",
doi = "10.1021/acs.jmedchem.9b00131",
language = "English",
volume = "62",
pages = "2798--2813",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Discovery of 2-(Imidazo[1,2-b]pyridazin-2-yl)acetic Acid as a New Class of Ligands Selective for the γ-Hydroxybutyric Acid (GHB) High-Affinity Binding Sites

AU - Krall, Jacob

AU - Bavo, Francesco

AU - Falk-Petersen, Christina B

AU - Jensen, Claus Hatt

AU - Nielsen, Julie Olsson

AU - Tian, Yongsong

AU - Anglani, Valeria

AU - Kongstad, Kenneth Thermann

AU - Piilgaard, Louise

AU - Nielsen, Birgitte

AU - Gloriam, David E

AU - Kehler, Jan

AU - Jensen, Anders A.

AU - Harpsøe, Kasper

AU - Wellendorph, Petrine

AU - Frølund, Bente

PY - 2019/3/14

Y1 - 2019/3/14

N2 - Gabazine, a GABAA receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance GHB. We herein report a study on the structural determinants of gabazine for binding to i) the orthosteric binding site of the GABAA receptor and ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogs with relatively high affinity (Ki 0.19-2.19 µM) and >50 times selectivity for the [3H]NCS-382 over [3H]muscimol binding sites. These results highlight that gabazine interacts with the high-affinity GHB and orthosteric GABAA receptor binding sites differently, and that distinct analogs can be generated to select between them. To facilitate further in vivo studies a promising prodrug candidate for brain delivery was identified.

AB - Gabazine, a GABAA receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance GHB. We herein report a study on the structural determinants of gabazine for binding to i) the orthosteric binding site of the GABAA receptor and ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2-b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogs with relatively high affinity (Ki 0.19-2.19 µM) and >50 times selectivity for the [3H]NCS-382 over [3H]muscimol binding sites. These results highlight that gabazine interacts with the high-affinity GHB and orthosteric GABAA receptor binding sites differently, and that distinct analogs can be generated to select between them. To facilitate further in vivo studies a promising prodrug candidate for brain delivery was identified.

U2 - 10.1021/acs.jmedchem.9b00131

DO - 10.1021/acs.jmedchem.9b00131

M3 - Journal article

C2 - 30763084

VL - 62

SP - 2798

EP - 2813

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -

ID: 213555678