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

Francesco Bavo, Heleen De-Jong, Jonas Petersen, Christina Birkedahl Falk-Petersen, Rebekka Löffler, Emma Sparrow, Frederik Rostrup, Jannik Nicklas Eliasen, Kristine S. Wilhelmsen, Kasper Barslund, Christoffer Bundgaard, Birgitte Nielsen, Uffe Kristiansen, Petrine Wellendorph, Yury Bogdanov, Bente Frølund*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

3 Citations (Scopus)

Abstract

The 3,9-diazaspiro[5.5]undecane-based compounds 2027 and 018 have previously been reported to be potent competitive ?-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 α4βδsubtype 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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume64
Issue number24
Pages (from-to)17795-17812
ISSN0022-2623
DOIs
Publication statusPublished - 2021

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