Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based γ-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect.

Autor:	Bavo F; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., de-Jong H; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Petersen J; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark., Falk-Petersen CB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Löffler R; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Sparrow E; Antibody and Vaccine Group, Centre for Cancer Immunology, MP127, University of Southampton Faculty of Medicine, Southampton, Hants SO16 6YD, United Kingdom., Rostrup F; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Eliasen JN; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Wilhelmsen KS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Barslund K; Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark., Bundgaard C; Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark., Nielsen B; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark., Kristiansen U; 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., Bogdanov Y; Antibody and Vaccine Group, Centre for Cancer Immunology, MP127, University of Southampton Faculty of Medicine, Southampton, Hants SO16 6YD, United Kingdom., 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] 2021 Dec 23; Vol. 64 (24), pp. 17795-17812. Date of Electronic Publication: 2021 Dec 15.
DOI:	10.1021/acs.jmedchem.1c00290
Abstrakt:	The 3,9-diazaspiro[5.5]undecane-based compounds 2027 and 018 have previously been reported to be potent competitive γ-aminobutyric acid type A receptor (GABA A R) antagonists showing low cellular membrane permeability. Given the emerging peripheral application of GABA A R ligands, we hypothesize 2027 analogs as promising lead structures for peripheral GABA A R inhibition. We herein report a study on the structural determinants of 2027 in order to suggest a potential binding mode as a basis for rational design. The study identified the importance of the spirocyclic benzamide, compensating for the conventional acidic moiety, for GABA A R ligands. The structurally simplified m -methylphenyl analog 1e displayed binding affinity in the high-nanomolar range ( K i = 180 nM) and was superior to 2027 and 018 regarding selectivity for the extrasynaptic α 4 βδ subtype versus the α 1 - and α 2 - containing subtypes. Importantly, 1e was shown to efficiently rescue inhibition of T cell proliferation, providing a platform to explore the immunomodulatory potential for this class of compounds.
Databáze:	MEDLINE
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