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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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

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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
Pages (from-to)2798-2813
ISSN0022-2623
DOIs
Publication statusPublished - 14 Mar 2019

ID: 213555678