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

Jacob Krall; Francesco Bavo; Christina B Falk-Petersen; Claus Hatt Jensen; Julie Olsson Nielsen; Yongsong Tian; Valeria Anglani; Kenneth Thermann Kongstad; Louise Piilgaard; Birgitte Nielsen; David E Gloriam; Jan Kehler; Anders A. Jensen; Kasper Harpsøe; Petrine Wellendorph; Bente Frølund

doi:10.1021/acs.jmedchem.9b00131

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

Jacob Krall, Francesco Bavo, Christina B Falk-Petersen, Claus Hatt Jensen, Julie Olsson Nielsen, Yongsong Tian, Valeria Anglani, Kenneth Thermann Kongstad, Louise Piilgaard, Birgitte Nielsen, David E Gloriam, Jan Kehler, Anders A. Jensen, Kasper Harpsøe, Petrine Wellendorph, Bente Frølund

Neuropharm and Genetics

3 Citations (Scopus)

Abstract

Gabazine, a γ-aminobutyric acid type A (GABA_A) 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 γ-hydroxybutyric acid (GHB). We herein report a study on the structural determinants of gabazine for binding to (i) the orthosteric binding site of the GABA_A 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 analogues with relatively high affinity (K_i 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 GABA_A receptor binding sites differently and that distinct analogues can be generated to select between them. To facilitate further in vivo studies, a promising prodrug candidate for brain delivery was identified.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	5
Pages (from-to)	2798-2813
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00131
Publication status	Published - 14 Mar 2019

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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

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 et al.
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

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

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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 γ-aminobutyric acid type 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 γ-hydroxybutyric acid (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 analogues 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 analogues 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",

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doi = "10.1021/acs.jmedchem.9b00131",

language = "English",

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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 γ-aminobutyric acid type 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 γ-hydroxybutyric acid (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 analogues 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 analogues 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 γ-aminobutyric acid type 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 γ-hydroxybutyric acid (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 analogues 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 analogues 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

SN - 0022-2623

VL - 62

SP - 2798

EP - 2813

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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

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