Covalent Inhibition of the Histamine H3 Receptor.
| Title: | Covalent Inhibition of the Histamine H3 Receptor. |
|---|---|
| Authors: | Wágner G; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Mocking TAM; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Kooistra AJ; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Slynko I; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Ábrányi-Balogh P; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.; Keserű GM; Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.; Wijtmans M; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Vischer HF; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; de Esch IJP; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.; Leurs R; Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. |
| Source: | Molecules (Basel, Switzerland) [Molecules] 2019 Dec 11; Vol. 24 (24). Date of Electronic Publication: 2019 Dec 11. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, c1995- |
| MeSH Terms: | Isothiocyanates/*chemical synthesis ; Receptors, Histamine H3/*metabolism ; Small Molecule Libraries/*chemical synthesis; Histamine Agonists/chemical synthesis ; Histamine Agonists/chemistry ; Histamine Agonists/pharmacology ; Histamine Antagonists/chemical synthesis ; Histamine Antagonists/chemistry ; Histamine Antagonists/pharmacology ; Isothiocyanates/chemistry ; Isothiocyanates/pharmacology ; Receptors, Histamine H3/chemistry ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Drug Inverse Agonism ; HEK293 Cells ; Humans ; Ligands |
| 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. |
| Competing Interests: | The authors declare no conflicts of interest. |
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| Grant Information: | 718.014.002 Nederlandse Organisatie voor Wetenschappelijk Onderzoek; PD124598 Hungarian Science Foundation OTKA |
| Contributed Indexing: | Keywords: G protein-coupled receptor (GPCR); Histamine H3 receptor; covalent binder; isothiocyanate |
| Substance Nomenclature: | 0 (Histamine Agonists); 0 (Histamine Antagonists); 0 (Isothiocyanates); 0 (Ligands); 0 (Receptors, Histamine H3); 0 (Small Molecule Libraries) |
| Entry Date(s): | Date Created: 20191215 Date Completed: 20200505 Latest Revision: 20200505 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC6943558 |
| DOI: | 10.3390/molecules24244541 |
| PMID: | 31835873 |
| Database: | MEDLINE |
Journal Article