Analysis of Multiple Histamine H-4 Receptor Compound Classes Uncovers G alpha(i) Protein- and beta-Arrestin2-Biased Ligands

作者：Nijmeijer Saskia; Vischer Henry F; Rosethorne Elizabeth M; Charlton Steven J; Leurs Rob^*

来源：Molecular Pharmacology, 2012, 82(6): 1174-1182.

DOI：10.1124/mol.112.080911

After the recent description of beta-arrestin2 recruitment to the human histamine H-4 receptor (hH(4)R) 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 hH(4)R ligands to induce G alpha(i) protein signaling and beta-arrestin2 recruitment by the hH(4)R. The selected hH(4)R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH(4)R ligands with a significant bias for the G alpha(i) protein or beta-arrestin2 pathway on the basis of efficacy differences. In addition, hH(4)R 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 G alpha(i) protein-biased or beta-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH(4)R ligands are important pharmacological tools to unravel the significance of biased hH(4)R signaling in H4R pharmacology.

• 出版日期2012-12