biostudies-literatureNijmeijer SDutch Research Council (NWO)89-100https://www.ebi.ac.uk/biostudies/studies/S-EPMC3764852biostudies-literatureUnknown170(1)<h4>Background and purpose</h4>The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H₄ receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E182(5.46) in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C98(3.36) in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98(3.36) by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research.<h4>Experimental approach</h4>We designed and synthesized VUF14480, and pharmacologically characterized this compBritish journal of pharmacologyDesign and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H₄ receptor.PMC3764852700.59.408Haaksma EESchultes Sde Graaf CNijmeijer SWijtmans MVischer HFLeurs Rvan de Stolpe ACLusink VEngelhardt Hde Esch IJStachurski KfalseDesign and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H₄ receptor.<h4>Background and purpose</h4>The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H₄ receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E182(5.46) in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C98(3.36) in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C98(3.36) by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research.<h4>Experimental approach</h4>We designed and synthesized VUF14480, and pharmacologically characterized this comp2013-01-01T00:00:00Z2013 Sep2026-05-06T21:35:13.007Z2026-04-07T22:21:39.073ZS-EPMC37648522334715910.1111/bph.12113