Molecular determinants of ligand binding to H4R species variants

Molecular Pharmacology
Herman D LimRob Leurs

Abstract

The histamine H(4) receptor (H(4)R) is the latest identified histamine receptor to emerge as a potential drug target for inflammatory diseases. Animal models are employed to validate this potential drug target. Concomitantly, various H(4)R orthologs have been cloned, including the human, mouse, rat, guinea pig, monkey, pig, and dog H(4)Rs. In this article, we expressed all these H(4)R orthologs in human embryonic kidney 293T cells and compared their interactions with currently used standard H(4)R ligands, including the H(4)R agonists histamine, 4-methylhistamine, guanidinylethyl isothiourea (VUF 8430), the H(4)R antagonists 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) and [(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine (VUF 6002), and the inverse H(4)R agonist thioperamide. Most of the evaluated ligands display significantly different affinities at the different H(4)R orthologs. These "natural mutants" of H(4)R were used to study ligand-receptor interactions by using chimeric human-pig-human and pig-human-pig H(4)R proteins and site-directed mutagenesis. Our results are a useful reference for ligand selection for studies in animal models of diseases and offer new insights in the understandi...Continue Reading

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Citations

Mar 2, 2011·Naunyn-Schmiedeberg's Archives of Pharmacology·David SchnellRoland Seifert
Jul 30, 2011·Naunyn-Schmiedeberg's Archives of Pharmacology·Irena BrunskoleArmin Buschauer
Oct 29, 2011·Naunyn-Schmiedeberg's Archives of Pharmacology·Heidrun ApplRoland Seifert
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Dec 12, 2012·Journal of Molecular Graphics & Modelling·Zhiwei FengYouyong Li
Jul 20, 2010·British Journal of Pharmacology·Vanina A Medina, Elena S Rivera
Jan 29, 2013·British Journal of Pharmacology·S NijmeijerR Leurs
May 30, 2013·British Journal of Pharmacology·A J KooistraC de Graaf
Sep 18, 2014·Chemical Biology & Drug Design·Michelle Fidelis Corrêa, João Paulo Dos Santos Fernandes
Dec 26, 2012·Drug Discovery Today·Chris de GraafIwan J P de Esch
Dec 30, 2014·Trends in Pharmacological Sciences·Vignir IsbergDavid E Gloriam
Oct 11, 2014·Naunyn-Schmiedeberg's Archives of Pharmacology·Monika FeliszekEberhard Schlicker
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Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Pakhuri MehtaSławomir Filipek
Jun 6, 2021·Journal of Labelled Compounds & Radiopharmaceuticals·Agnieszka ZakJohnny Vercouillie
May 19, 2020·Journal of Medicinal Chemistry·Edith BartoleGünther Bernhardt
Oct 24, 2018·Journal of Medicinal Chemistry·Márton VassChris de Graaf

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