Cargando…
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(3) receptor (H(3)R). Starting from...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943558/ https://www.ncbi.nlm.nih.gov/pubmed/31835873 http://dx.doi.org/10.3390/molecules24244541 |
_version_ | 1783484902445940736 |
---|---|
author | 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 |
author_facet | 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 |
author_sort | Wágner, Gábor |
collection | PubMed |
description | 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(3) receptor (H(3)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(3)R 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 H(3)R was validated with washout experiments and leads to inverse agonism on H(3)R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H(3)R conformation and to study the consequences of prolonged inhibition of the H(3)R. |
format | Online Article Text |
id | pubmed-6943558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69435582020-01-10 Covalent Inhibition of the Histamine H(3) Receptor 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 Molecules Article 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(3) receptor (H(3)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(3)R 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 H(3)R was validated with washout experiments and leads to inverse agonism on H(3)R. Irreversible binder 44 (VUF15662) may serve as a useful tool compound to stabilize the inactive H(3)R conformation and to study the consequences of prolonged inhibition of the H(3)R. MDPI 2019-12-11 /pmc/articles/PMC6943558/ /pubmed/31835873 http://dx.doi.org/10.3390/molecules24244541 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 Covalent Inhibition of the Histamine H(3) Receptor |
title | Covalent Inhibition of the Histamine H(3) Receptor |
title_full | Covalent Inhibition of the Histamine H(3) Receptor |
title_fullStr | Covalent Inhibition of the Histamine H(3) Receptor |
title_full_unstemmed | Covalent Inhibition of the Histamine H(3) Receptor |
title_short | Covalent Inhibition of the Histamine H(3) Receptor |
title_sort | covalent inhibition of the histamine h(3) receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943558/ https://www.ncbi.nlm.nih.gov/pubmed/31835873 http://dx.doi.org/10.3390/molecules24244541 |
work_keys_str_mv | AT wagnergabor covalentinhibitionofthehistamineh3receptor AT mockingtamaraam covalentinhibitionofthehistamineh3receptor AT kooistraalbertj covalentinhibitionofthehistamineh3receptor AT slynkoinna covalentinhibitionofthehistamineh3receptor AT abranyibaloghpeter covalentinhibitionofthehistamineh3receptor AT keserugyorgym covalentinhibitionofthehistamineh3receptor AT wijtmansmaikel covalentinhibitionofthehistamineh3receptor AT vischerhenryf covalentinhibitionofthehistamineh3receptor AT deeschiwanjp covalentinhibitionofthehistamineh3receptor AT leursrob covalentinhibitionofthehistamineh3receptor |