Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues.

Authors: Nijmeijer S, Vischer HF, Sirci F, Schultes S, Engelhardt H, de Graaf C, Rosethorne EM, Charlton SJ and Leurs R.
Publisher/Year: Br J Pharmacol 170(1):78-88.
Pub Med ID/Journal ID: PMID:23351115



The histamine H₄ receptor, originally thought to signal merely through Gαi proteins, has recently been shown to also recruit and signal via β-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in β-arrestin2 recruitment, we have identified additional biased hH₄R ligands that preferentially couple to Gαi or β-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH₄R signalling.


We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH₄R-mediated Gαi protein signalling or β-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure-activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH₄R homology model was used to identify receptor regions important for biased hH₄R signalling.


One indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gαi and β-arrestin2 pathway and was classified as unbiased hH₄R ligand. The other 47 indolecarboxamides were β-arrestin2-biased agonists. Intrinsic activities of the unbiased as well as β-arrestin2-biased indolecarboxamides to induce β-arrestin2 recruitment could be correlated with different ligand features and hH₄R regions.


Small structural modifications resulted in diverse intrinsic activities for unbiased (75) and β-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-β-arrestin2 recruitment. This knowledge is useful for the design of hH₄R ligands with biased intrinsic activities and aids our understanding of the mechanism of H₄R activation.