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.
Original language | English |
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Article number | 4541 |
Pages (from-to) | 1-19 |
Number of pages | 19 |
Journal | Molecules |
Volume | 24 |
Issue number | 24 |
DOIs | |
Publication status | Published - 11 Dec 2019 |
Funding
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.
Funders | Funder number |
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Hungarian Science Foundation OTKA | |
Netherlands Organization for Scientific Research | |
The Netherlands Organization for Scientific Research | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 718.014.002 |
Hungarian Science Foundation | PD124598 |
Keywords
- Covalent binder
- G protein-coupled receptor (GPCR)
- Histamine H receptor
- Isothiocyanate