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

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.