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Open AccessArticle

Covalent Inhibition of the Histamine H3 Receptor

1
Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
2
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(24), 4541; https://doi.org/10.3390/molecules24244541
Received: 17 November 2019 / Revised: 6 December 2019 / Accepted: 8 December 2019 / Published: 11 December 2019
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
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. View Full-Text
Keywords: G protein-coupled receptor (GPCR); Histamine H3 receptor; covalent binder; isothiocyanate G protein-coupled receptor (GPCR); Histamine H3 receptor; covalent binder; isothiocyanate
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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. Covalent Inhibition of the Histamine H3 Receptor. Molecules 2019, 24, 4541.

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