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.

Autor: Krall J; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Bavo F; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark.; Department of Pharmaceutical Sciences , University of Milan , via Mangiagalli 25 , 20133 Milano , Italy., Falk-Petersen CB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Jensen CH; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Nielsen JO; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Tian Y; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Anglani V; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Kongstad KT; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Piilgaard L; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Nielsen B; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Gloriam DE; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Kehler J; Discovery Chemistry and DMPK , H. Lundbeck A/S , Ottiliavej, DK-2500 Valby , Denmark., Jensen AA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Harpsøe K; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Wellendorph P; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark., Frølund B; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Mar 14; Vol. 62 (5), pp. 2798-2813. Date of Electronic Publication: 2019 Feb 27.
DOI: 10.1021/acs.jmedchem.9b00131
Abstrakt: Gabazine, a γ-aminobutyric acid type A (GABA A ) receptor antagonist, has previously been reported to inhibit the binding of [ 3 H]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 [ 3 H]NCS-382 over [ 3 H]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.
Databáze: MEDLINE
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