Covalent inhibition of the histamine H3 receptor

Gábor Wágner, Tamara A.M. Mocking, Albert J. Kooistra, Inna Slynko, Péter Ábrányi-Balogh, György M. Keser u, Maikel Wijtmans, Henry F. Vischer, Iwan J.P. de Esch, Rob Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number4541
Pages (from-to)1-19
Number of pages19
Issue number24
Publication statusPublished - 11 Dec 2019


Funding: This research was funded by The Netherlands Organization for Scientific Research (NWO) TOPPUNT [“7 ways to 7TMR modulation (7-to-7)”] [Grant 718.014.002]. P. Ábrányi-Balogh was supported by the Hungarian Science Foundation OTKA (PD124598) grant.

FundersFunder number
Hungarian Science Foundation OTKA
Netherlands Organization for Scientific Research
The Netherlands Organization for Scientific Research
Nederlandse Organisatie voor Wetenschappelijk Onderzoek718.014.002
Hungarian Science FoundationPD124598


    • Covalent binder
    • G protein-coupled receptor (GPCR)
    • Histamine H receptor
    • Isothiocyanate


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