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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect. / Bavo, Francesco; De-Jong, Heleen; Petersen, Jonas; Falk-Petersen, Christina Birkedahl; Löffler, Rebekka; Sparrow, Emma; Rostrup, Frederik; Eliasen, Jannik Nicklas; Wilhelmsen, Kristine S.; Barslund, Kasper; Bundgaard, Christoffer; Nielsen, Birgitte; Kristiansen, Uffe; Wellendorph, Petrine; Bogdanov, Yury; Frølund, Bente.

In: Journal of Medicinal Chemistry, Vol. 64, No. 24, 2021, p. 17795-17812.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bavo, F, De-Jong, H, Petersen, J, Falk-Petersen, CB, Löffler, R, Sparrow, E, Rostrup, F, Eliasen, JN, Wilhelmsen, KS, Barslund, K, Bundgaard, C, Nielsen, B, Kristiansen, U, Wellendorph, P, Bogdanov, Y & Frølund, B 2021, 'Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect', Journal of Medicinal Chemistry, vol. 64, no. 24, pp. 17795-17812. https://doi.org/10.1021/acs.jmedchem.1c00290

APA

Bavo, F., De-Jong, H., Petersen, J., Falk-Petersen, C. B., Löffler, R., Sparrow, E., Rostrup, F., Eliasen, J. N., Wilhelmsen, K. S., Barslund, K., Bundgaard, C., Nielsen, B., Kristiansen, U., Wellendorph, P., Bogdanov, Y., & Frølund, B. (2021). Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect. Journal of Medicinal Chemistry, 64(24), 17795-17812. https://doi.org/10.1021/acs.jmedchem.1c00290

Vancouver

Bavo F, De-Jong H, Petersen J, Falk-Petersen CB, Löffler R, Sparrow E et al. Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect. Journal of Medicinal Chemistry. 2021;64(24):17795-17812. https://doi.org/10.1021/acs.jmedchem.1c00290

Author

Bavo, Francesco ; De-Jong, Heleen ; Petersen, Jonas ; Falk-Petersen, Christina Birkedahl ; Löffler, Rebekka ; Sparrow, Emma ; Rostrup, Frederik ; Eliasen, Jannik Nicklas ; Wilhelmsen, Kristine S. ; Barslund, Kasper ; Bundgaard, Christoffer ; Nielsen, Birgitte ; Kristiansen, Uffe ; Wellendorph, Petrine ; Bogdanov, Yury ; Frølund, Bente. / Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect. In: Journal of Medicinal Chemistry. 2021 ; Vol. 64, No. 24. pp. 17795-17812.

Bibtex

@article{b9ba9639919e4bbf88b16591fc37afb1,
title = "Structure-Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based ?-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect",
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. ",
author = "Francesco Bavo and Heleen De-Jong and Jonas Petersen and Falk-Petersen, {Christina Birkedahl} and Rebekka L{\"o}ffler and Emma Sparrow and Frederik Rostrup and Eliasen, {Jannik Nicklas} and Wilhelmsen, {Kristine S.} and Kasper Barslund and Christoffer Bundgaard and Birgitte Nielsen and Uffe Kristiansen and Petrine Wellendorph and Yury Bogdanov and Bente Fr{\o}lund",
note = "Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",
year = "2021",
doi = "10.1021/acs.jmedchem.1c00290",
language = "English",
volume = "64",
pages = "17795--17812",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "24",

}

RIS

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 -

ID: 288924383