Covalent Inhibition of the Histamine H3 Receptor

Molecules. 2019 Dec 11;24(24):4541. doi: 10.3390/molecules24244541.


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.

Keywords: G protein-coupled receptor (GPCR); Histamine H3 receptor; covalent binder; isothiocyanate.

MeSH terms

  • 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


  • Histamine Agonists
  • Histamine Antagonists
  • Isothiocyanates
  • Ligands
  • Receptors, Histamine H3
  • Small Molecule Libraries