Covalent Inhibition of the Histamine H3 Receptor

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...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2019-12, Vol.24 (24), p.4541
Main Authors: 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
Format: Article
Language:English
Subjects:
Amination
Binding sites
Central nervous system
Cerebral cortex
Chemical bonds
Covalence
Design
Fluorides
Food intake
Food processing
Histamine H3 receptors
Hypothalamus
Hypothalamus (lateral)
Intermediates
Kinases
Ligands
Neostriatum
Piperazine
Proteins
Seizures
Selectivity
Sleep
Sleep and wakefulness
Substitutes
Tuberomammillary nucleus
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules24244541