Nijmeijer, S, Vischer, H, Sirci, F, Schultes, S, Engelhardt, H, de Graaf, C, Rosethorne, Elizabeth, Charlton, Steven and Leurs, R (2013) Detailed analysis of biased histamine H4 receptor signalling by JNJ7777120 analogues. British Journal of Pharmacology, 170. pp. 78-88.

Abstract

BACKGROUND AND PURPOSE:
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 hH4 R ligands that preferentially couple to Gαi or β-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH4 R signalling.

EXPERIMENTAL APPROACH:
We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH4 R-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 hH4 R homology model was used to identify receptor regions important for biased hH4 R signalling.

KEY RESULTS:
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 hH4 R 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 hH4 R regions.

CONCLUSION AND IMPLICATIONS:
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 hH4 R ligands with biased intrinsic activities and aids our understanding of the mechanism of H4 R activation.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9083