Covalent Inhibition of the Histamine H 3 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 H receptor (H R). Starting from a 2-...

Full description

Saved in:
Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2019-12, Vol.24 (24)
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:
Drug Inverse Agonism
HEK293 Cells
Histamine Agonists - chemical synthesis
Histamine Agonists - chemistry
Histamine Agonists - pharmacology
Histamine Antagonists - chemical synthesis
Histamine Antagonists - chemistry
Histamine Antagonists - pharmacology
Humans
Isothiocyanates - chemical synthesis
Isothiocyanates - chemistry
Isothiocyanates - pharmacology
Ligands
Receptors, Histamine H3 - chemistry
Receptors, Histamine H3 - metabolism
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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 H receptor (H R). 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 H R ligand . 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 with H R was validated with washout experiments and leads to inverse agonism on H R. Irreversible binder (VUF15662) may serve as a useful tool compound to stabilize the inactive H R conformation and to study the consequences of prolonged inhibition of the H R.
ISSN:1420-3049
DOI:10.3390/molecules24244541