Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues. (15th August 2013)

• Record Type: Journal Article
• Authors: Nijmeijer, S; Vischer, H F; Sirci, F; Schultes, S; Engelhardt, H; de, C; Rosethorne, E M; Charlton, S J; Leurs, R
• Is Part Of: British journal of pharmacology. Volume 170:Number 1(2013:Sep.)
• Page Start: 78
• Page End: 88
• Publication Date: 2013-08-15
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12117
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12117-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The histamine H<sub>4</sub> receptor, originally thought to signal merely through Gα<sub>i</sub> 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 hH<sub>4</sub>R ligands that preferentially couple to Gα<sub>i</sub> or β‐arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH<sub>4</sub>R signalling.</p> </sec> <sec id="bph12117-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH<sub>4</sub>R‐mediated Gα<sub>i</sub> 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 hH<sub>4</sub>R homology model was used to identify receptor regions important for biased hH<sub>4</sub>R signalling.</p> </sec> <sec id="bph12117-sec-0003" sec-type="section"> <title>Key Results</title> <p>One indolecarboxamide (<bold>75</bold>) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gα<sub>i</sub> and β‐arrestin2 pathway and was classified as unbiased hH<sub>4</sub>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 hH<sub>4</sub>R regions.</p> </sec> <sec id="bph12117-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>Small structural modifications resulted in diverse intrinsic activities for unbiased (<bold>75</bold>) 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 hH<sub>4</sub>R ligands with biased intrinsic activities and aids our understanding of the mechanism of H<sub>4</sub>R activation.</p> </sec> <sec id="bph12117-sec-1001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue‐1</p> </sec> </abstract>