Abstract
Astemizole, a H1R antagonist shows high affinity to the histamine H-1 receptor but only a moderate affinity to the histamine H-4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H-1 receptor and to increase affinity to the histamine H-4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized ...
Abstract
Astemizole, a H1R antagonist shows high affinity to the histamine H-1 receptor but only a moderate affinity to the histamine H-4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H-1 receptor and to increase affinity to the histamine H-4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H-1 and H-4 receptors. The new compounds show affinity to the histamine H-1 receptor in the pK (i) range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H-4 receptor was surprisingly rather low (pK (i) from 4.4 to 5.6). Three representative compounds were docked into the histamine H-1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H-4 receptor, a H-1/H-4-pharmacophore hypothesis was developed.
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