Covalent Inhibition of the Histamine H3 Receptor

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

Standard

Covalent Inhibition of the Histamine H3 Receptor. / Wágner, Gábor; Mocking, Tamara A M; Kooistra, Albert J; Slynko, Inna; Ábrányi-Balogh, Péter; Keserű, György M; Wijtmans, Maikel; Vischer, Henry F; de Esch, Iwan J P; Leurs, Rob.

In: Molecules (Print Archive Edition), Vol. 24, 4541, 11.12.2019.

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

Harvard

Wágner, G, Mocking, TAM, Kooistra, AJ, Slynko, I, Ábrányi-Balogh, P, Keserű, GM, Wijtmans, M, Vischer, HF, de Esch, IJP & Leurs, R 2019, 'Covalent Inhibition of the Histamine H3 Receptor', Molecules (Print Archive Edition), vol. 24, 4541. https://doi.org/10.3390/molecules24244541

APA

Wágner, G., Mocking, T. A. M., Kooistra, A. J., Slynko, I., Ábrányi-Balogh, P., Keserű, G. M., Wijtmans, M., Vischer, H. F., de Esch, I. J. P., & Leurs, R. (2019). Covalent Inhibition of the Histamine H3 Receptor. Molecules (Print Archive Edition), 24, [4541]. https://doi.org/10.3390/molecules24244541

Vancouver

Wágner G, Mocking TAM, Kooistra AJ, Slynko I, Ábrányi-Balogh P, Keserű GM et al. Covalent Inhibition of the Histamine H3 Receptor. Molecules (Print Archive Edition). 2019 Dec 11;24. 4541. https://doi.org/10.3390/molecules24244541

Author

Wágner, Gábor ; Mocking, Tamara A M ; Kooistra, Albert J ; Slynko, Inna ; Ábrányi-Balogh, Péter ; Keserű, György M ; Wijtmans, Maikel ; Vischer, Henry F ; de Esch, Iwan J P ; Leurs, Rob. / Covalent Inhibition of the Histamine H3 Receptor. In: Molecules (Print Archive Edition). 2019 ; Vol. 24.

Bibtex

@article{9d8f46aeb53948099551a3c1309c1e4d,
title = "Covalent Inhibition of the Histamine H3 Receptor",
abstract = "Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.",
author = "G{\'a}bor W{\'a}gner and Mocking, {Tamara A M} and Kooistra, {Albert J} and Inna Slynko and P{\'e}ter {\'A}br{\'a}nyi-Balogh and Keser{\H u}, {Gy{\"o}rgy M} and Maikel Wijtmans and Vischer, {Henry F} and {de Esch}, {Iwan J P} and Rob Leurs",
year = "2019",
month = dec,
day = "11",
doi = "10.3390/molecules24244541",
language = "English",
volume = "24",
journal = "Molecules (Print Archive Edition)",
issn = "1431-5157",
publisher = "M D P I AG",

}

RIS

TY - JOUR

T1 - Covalent Inhibition of the Histamine H3 Receptor

AU - Wágner, Gábor

AU - Mocking, Tamara A M

AU - Kooistra, Albert J

AU - Slynko, Inna

AU - Ábrányi-Balogh, Péter

AU - Keserű, György M

AU - Wijtmans, Maikel

AU - Vischer, Henry F

AU - de Esch, Iwan J P

AU - Leurs, Rob

PY - 2019/12/11

Y1 - 2019/12/11

N2 - Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.

AB - Covalent binding of G protein-coupled receptors by small molecules is a useful approach for better understanding of the structure and function of these proteins. We designed, synthesized and characterized a series of 6 potential covalent ligands for the histamine H3 receptor (H3R). Starting from a 2-amino-pyrimidine scaffold, optimization of anchor moiety and warhead followed by fine-tuning of the required reactivity via scaffold hopping resulted in the isothiocyanate H3R ligand 44. It shows high reactivity toward glutathione combined with appropriate stability in water and reacts selectively with the cysteine sidechain in a model nonapeptide equipped with nucleophilic residues. The covalent interaction of 44 with H3R was validated with washout experiments and leads to inverse agonism on H3R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H3R conformation and to study the consequences of prolonged inhibition of the H3R.

U2 - 10.3390/molecules24244541

DO - 10.3390/molecules24244541

M3 - Journal article

C2 - 31835873

VL - 24

JO - Molecules (Print Archive Edition)

JF - Molecules (Print Archive Edition)

SN - 1431-5157

M1 - 4541

ER -

ID: 235971991