A three-dimensional homology model of the human histamine H 4 receptor was developed to investigate the binding mode of a series of structurally diverse H 4-agonists, i.e. histamine, clozapine, and the recently described selective, nonimidazole agonist VUF 8430. Mutagenesis studies and docking of these ligands in a rhodopsin-based homology model revealed two essential points of interactions in the binding pocket, i.e. Asp3.32 and Glu5.46 (Ballesteros-Weinstein numbering system). It is postulated that Asp3.32 interacts in its anionic state, whereas Glu5.46 interacts in its neutral form. The hypothesis was tested with the point mutations D3.32N and E5.46Q. For the D3.32N no binding affinity toward any of the ligands could be detected. This is in sharp contrast to the E5.46Q mutant, which discriminates between various ligands. The affinity of histamine-like ligands was decreased approximately a 1000-fold, whereas the affinity of all other ligands remained virtually unchanged. The proposed model for agonist binding as well as ab initio calculations for histamine and VUF 8430 explain the observed differences in binding to the H 4R mutants. These studies provide a molecular understanding for the action of a variety of H 4 receptor-ligands. The resulting H 4 receptor model will be the basis for the development of new H 4 receptor-ligands.
From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H(4)R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (VUF10497, 55) as potent human H(4)R inverse agonists (pK(i) = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H(1) receptor (H(1)R) and therefore represent a novel class of dual action H(1)R/H(4)R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H(4)R and were found to possess anti-inflammatory properties in vivo in the rat.
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