TY - JOUR
T1 - Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect
AU - Bavo, Francesco
AU - De-Jong, Heleen
AU - Petersen, Jonas
AU - Falk-Petersen, Christina Birkedahl
AU - Löffler, Rebekka
AU - Sparrow, Emma
AU - Rostrup, Frederik
AU - Eliasen, Jannik Nicklas
AU - Wilhelmsen, Kristine S.
AU - Barslund, Kasper
AU - Bundgaard, Christoffer
AU - Nielsen, Birgitte
AU - Kristiansen, Uffe
AU - Wellendorph, Petrine
AU - Bogdanov, Yury
AU - Frølund, Bente
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.1c00290
DO - 10.1021/acs.jmedchem.1c00290
M3 - Journal article
C2 - 34908407
AN - SCOPUS:85121929031
VL - 64
SP - 17795
EP - 17812
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 24
ER -