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. 2012 Dec;82(6):1174-82.
doi: 10.1124/mol.112.080911. Epub 2012 Sep 12.

Analysis of multiple histamine H₄ receptor compound classes uncovers Gαi protein- and β-arrestin2-biased ligands

Saskia Nijmeijer  1 , Henry F Vischer, Elizabeth M Rosethorne, Steven J Charlton, Rob Leurs
Affiliations

Analysis of multiple histamine H₄ receptor compound classes uncovers Gαi protein- and β-arrestin2-biased ligands

Saskia Nijmeijer et al. Mol Pharmacol. 2012 Dec.

Abstract

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 Gα(i) protein signaling and β-arrestin2 recruitment by the hH₄R. The selected hH(4)R 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 Gα(i) 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 Gα(i) 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.

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