TY - JOUR T1 - Molecular Determinants of Ligand Binding to H<sub>4</sub>R Species Variants JF - Molecular Pharmacology JO - Mol Pharmacol SP - 734 LP - 743 DO - 10.1124/mol.109.063040 VL - 77 IS - 5 AU - Herman D. Lim AU - Chris de Graaf AU - Wen Jiang AU - Payman Sadek AU - Patricia M. McGovern AU - Enade P. Istyastono AU - Remko A. Bakker AU - Iwan J. P. de Esch AU - Robin L. Thurmond AU - Rob Leurs Y1 - 2010/05/01 UR - http://molpharm.aspetjournals.org/content/77/5/734.abstract N2 - The histamine H4 receptor (H4R) 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 H4R orthologs have been cloned, including the human, mouse, rat, guinea pig, monkey, pig, and dog H4Rs. In this article, we expressed all these H4R orthologs in human embryonic kidney 293T cells and compared their interactions with currently used standard H4R ligands, including the H4R agonists histamine, 4-methylhistamine, guanidinylethyl isothiourea (VUF 8430), the H4R 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 H4R agonist thioperamide. Most of the evaluated ligands display significantly different affinities at the different H4R orthologs. These “natural mutants” of H4R were used to study ligand-receptor interactions by using chimeric human-pig-human and pig-human-pig H4R 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 understanding of H4R-ligand receptor interactions.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics ER -