Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Journal of Medicinal Chemistry |
Vol/bind | 64 |
Udgave nummer | 24 |
Sider (fra-til) | 17795-17812 |
ISSN | 0022-2623 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This work was supported by the Lundbeck Foundation (R303-2018-3346 and R230-2026-2562) and the Novo Nordisk Foundation (NNF21OC0067835 to P.W.). Y.B. and E.L.S. were supported by the Cancer Research UK Pioneer Award to Y.B. (C55651/A26704). Also, we thank the Drug Research Academy graduate programme.
Publisher Copyright:
© 2021 American Chemical Society.
ID: 288924383