Document Detail


Detailed analysis of biased histamine H(4) receptor signalling by JNJ 7777120 analogues.
MedLine Citation:
PMID:  23351115     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
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.
Affiliation:
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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