RT Journal Article
SR Electronic
T1 Analysis of Multiple Histamine H<sub>4</sub> Receptor Compound Classes Uncovers Gα<sub>i</sub> Protein- and β-Arrestin2-Biased Ligands
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1174
OP 1182
DO 10.1124/mol.112.080911
VO 82
IS 6
A1 Saskia Nijmeijer
A1 Henry F. Vischer
A1 Elizabeth M. Rosethorne
A1 Steven J. Charlton
A1 Rob Leurs
YR 2012
UL http://molpharm.aspetjournals.org/content/82/6/1174.abstract
AB After the recent description of β-arrestin2 recruitment to the human histamine H4 receptor (hH4R) in response to the well known H4R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH4R ligands to induce Gαi protein signaling and β-arrestin2 recruitment by the hH4R. The selected hH4R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH4R ligands with a significant bias for the Gαi protein or β-arrestin2 pathway on the basis of efficacy differences. In addition, hH4R antagonists that did not show positive efficacy in either functional readouts were found. A common trend in pathway preference for the nine different ligand classes could not be observed. In particular, the isothiourea class shows very diverse results, varying from Gαi protein-biased or β-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH4R ligands are important pharmacological tools to unravel the significance of biased hH4R signaling in H4R pharmacology.