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Detailed analysis of biased histamine H(4) receptor signalling by JNJ 7777120 analogues.
MedLine Citation:
PMID:  23351115     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: The histamine H(4) receptor, originally thought to signal merely through Gα(i) -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(4) R ligands that preferentially couple to Gα(i) or β-arrestin2 proteins. In this study we explored ligand and receptor regions that are important for biased hH(4) R signalling. EXPERIMENTAL APPROACH: We evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH(4) R-mediated Gα(i) -protein signalling or β-arrestin2 recruitment. Subsequently, a FLAP 3D-QSAR analysis correlated intrinsic activity values to structural ligand requirements. Moreover, a hH(4) R homology model was used to identify receptor regions important for biased hH(4) R signalling. KEY RESULTS: One indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gα(i) and β-arrestin2 pathway and was classified as unbiased hH(4) 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 to different ligand features and hH(4) R regions. CONCLUSION AND IMPLICATIONS: Small structural modifications result 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 hH(4) R ligands with biased intrinsic activities and aids our understanding of the mechanism of H(4) R activation.
S Nijmeijer; H F Vischer; F Sirci; S Schultes; H Engelhardt; C de Graaf; E M Rosethorne; S J Charlton; R Leurs
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-28
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS),, VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
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