Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor--H1/H4 receptor selectivity.
Astemizole, a H1R antagonist shows high affinity to the histamine H1 receptor but only a moderate affinity to the histamine H4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H1 receptor and to increase affinity to the histamine H4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H1 and H4 receptors. The new compounds show affinity to the histamine H1 receptor in the pK i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H4 receptor was surprisingly rather low (pK i from 4.4 to 5.6). Three representative compounds were docked into the histamine H1 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 H4 receptor, a H1/H4-pharmacophore hypothesis was developed.
Department of Pharmaceutical/Medicinal Chemistry I, Institute of Pharmacy, University of Regensburg, 93040, Regensburg, Germany.
Eva
E
Wagner
Hans-Joachim
HJ
Wittmann
Sigurd
S
Elz
Andrea
A
Strasser
D000818:Animals; D016589:Astemizole / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D061987:Sf9 Cells; D018411:Spodoptera
C418607:HRH4 protein, human; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007211:Indoles; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D016589:Astemizole