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

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

  • J Med Chem. 2021 Dec 23;64(24):17795-17812. doi: 10.1021/acs.jmedchem.1c00290.
Francesco Bavo 1,  Heleen de-Jong 1,  Jonas Petersen 1 2,  Christina Birkedahl Falk-Petersen 1,  Rebekka Löffler 1,  Emma Sparrow 3,  Frederik Rostrup 1,  Jannik Nicklas Eliasen 1,  Kristine S Wilhelmsen 1,  Kasper Barslund 4,  Christoffer Bundgaard 4,  Birgitte Nielsen 1,  Uffe Kristiansen 1,  Petrine Wellendorph 1,  Yury Bogdanov 3,  Bente Frølund 1
Affiliations

Affiliations

  • 1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
  • 3 Antibody and Vaccine Group, Centre for Cancer Immunology, MP127, University of Southampton Faculty of Medicine, Southampton, Hants SO16 6YD, United Kingdom.
  • 4 Translational DMPK, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
PMID: 34908407 DOI: 10.1021/acs.jmedchem.1c00290
Abstract

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 (GABAAR) antagonists showing low cellular membrane permeability. Given the emerging peripheral application of GABAAR ligands, we hypothesize 2027 analogs as promising lead structures for peripheral GABAAR 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 GABAAR ligands. The structurally simplified m-methylphenyl analog 1e displayed binding affinity in the high-nanomolar range (Ki = 180 nM) and was superior to 2027 and 018 regarding selectivity for the extrasynaptic α4βδ subtype versus the α1- and α2- 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.

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