Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Analysis of Multiple Histamine H4 Receptor Compound Classes Uncovers Gαi Protein- and β-Arrestin2-Biased Ligands

Saskia Nijmeijer, Henry F. Vischer, Elizabeth M. Rosethorne, Steven J. Charlton and Rob Leurs
Molecular Pharmacology December 2012, 82 (6) 1174-1182; DOI: https://doi.org/10.1124/mol.112.080911
Saskia Nijmeijer
VU University Amsterdam, Amsterdam, The Netherlands (S.N., H.F.V., R.L.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (E.M.R., S.J.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henry F. Vischer
VU University Amsterdam, Amsterdam, The Netherlands (S.N., H.F.V., R.L.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (E.M.R., S.J.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth M. Rosethorne
VU University Amsterdam, Amsterdam, The Netherlands (S.N., H.F.V., R.L.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (E.M.R., S.J.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven J. Charlton
VU University Amsterdam, Amsterdam, The Netherlands (S.N., H.F.V., R.L.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (E.M.R., S.J.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rob Leurs
VU University Amsterdam, Amsterdam, The Netherlands (S.N., H.F.V., R.L.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (E.M.R., S.J.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

After the recent description of β-arrestin2 recruitment to the human histamine H4 receptor (hH4R) in response to the well known H4R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH4R ligands to induce Gαi protein signaling and β-arrestin2 recruitment by the hH4R. The selected hH4R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH4R ligands with a significant bias for the Gαi protein or β-arrestin2 pathway on the basis of efficacy differences. In addition, hH4R antagonists that did not show positive efficacy in either functional readouts were found. A common trend in pathway preference for the nine different ligand classes could not be observed. In particular, the isothiourea class shows very diverse results, varying from Gαi protein-biased or β-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH4R ligands are important pharmacological tools to unravel the significance of biased hH4R signaling in H4R pharmacology.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • S.N., H.F.V., and R.L. participate in the European COST BM0806.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080911.

  • ABBREVIATIONS:

    H4R
    histamine H4 receptor
    hH4R
    human histamine H4 receptor
    GPCR
    G protein-coupled receptor
    ERK
    extracellular signal-regulated kinase
    PTx
    pertussis toxin
    EFC
    enzyme fragment complementation
    JNJ 7777120
    1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine
    HEK293T
    human embryonic kidney cells expressing the large T-antigen of simian virus 40
    CRE
    cAMP response element
    4-MeHA
    4-methylhistamine.

  • Received June 29, 2012.
  • Accepted September 12, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Analysis of Multiple Histamine H4 Receptor Compound Classes Uncovers Gαi Protein- and β-Arrestin2-Biased Ligands
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Distinct Pluridimensional Efficacies of hH4R Ligands

Saskia Nijmeijer, Henry F. Vischer, Elizabeth M. Rosethorne, Steven J. Charlton and Rob Leurs
Molecular Pharmacology December 1, 2012, 82 (6) 1174-1182; DOI: https://doi.org/10.1124/mol.112.080911

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Distinct Pluridimensional Efficacies of hH4R Ligands

Saskia Nijmeijer, Henry F. Vischer, Elizabeth M. Rosethorne, Steven J. Charlton and Rob Leurs
Molecular Pharmacology December 1, 2012, 82 (6) 1174-1182; DOI: https://doi.org/10.1124/mol.112.080911
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Effects of Small Molecule Ligands on ACKR3 Receptors
  • Michaelis-Menten Quantification of GPCR-G Protein Signaling
  • Anti-aromatase activity of exemestane phase II metabolites
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2022 by the American Society for Pharmacology and Experimental Therapeutics