| Detailed analysis of biased histamine H(4) receptor signalling by JNJ 7777120 analogues. | |
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MedLine Citation:
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PMID: 23351115 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2013-1-28 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society. |
Affiliation:
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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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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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