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
Rapid CommunicationAccelerated Communication

Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive Activity

Pingwei Zhao, Haleli Sharir, Ankur Kapur, Alan Cowan, Ellen B. Geller, Martin W. Adler, Herbert H. Seltzman, Patricia H. Reggio, Susanne Heynen-Genel, Michelle Sauer, Thomas D.Y. Chung, Yushi Bai, Wei Chen, Marc G. Caron, Larry S. Barak and Mary E. Abood
Molecular Pharmacology October 2010, 78 (4) 560-568; DOI: https://doi.org/10.1124/mol.110.066746
Pingwei Zhao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haleli Sharir
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ankur Kapur
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan Cowan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ellen B. Geller
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin W. Adler
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Herbert H. Seltzman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Patricia H. Reggio
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Heynen-Genel
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Sauer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas D.Y. Chung
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yushi Bai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wei Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marc G. Caron
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Larry S. Barak
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mary E. Abood
  • 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
Loading

Abstract

Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics oxantel pamoate and pyrantel pamoate; the psychoactive compounds hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a Gi/o-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of β-arrestin2 to GPR35, and internalization of GPR35. In mice, it attenuates visceral pain perception, indicating an antinociceptive effect, possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35-associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent.

Footnotes

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

  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA023204, DA05274, DA029432, DA022950, and DA013429]. The HCS screening portion of this work was supported by the National Institutes of Health National Human Genome Research Institute Roadmap Initiative [Grant U54-HG003916] and performed at Sanford-Burnham's Conrad Prebys Center for Chemical Genomics (CPCCG), part of the Molecular Libraries Probe Production Centers Network (MLPCN) supported by the National Institutes of Health National Institute of Mental Health [Grant X01-MH085708].

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

    doi:10.1124/mol.110.066746.

  • ABBREVIATIONS:

    GPCR
    G-protein-coupled receptor
    NPPB
    5-nitro-2-(3-phenylpropylamino) benzoic acid
    HEK
    human embryonic kidney
    ERK1/2
    extracellular signal-regulated kinase
    DMEM
    Dulbecco's modified Eagle's medium
    HBSS
    Hanks' balanced salt solution
    WIN55212-2
    (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinylmethyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone
    CP55940
    (−)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxyl propyl] cyclohexan-1-ol
    O-1602
    5-methyl-4-[(1R,6R)-3-methyl-6-(1-methylenyl)-2-cyclohexen-1-yl]-1,3-benzenediol
    JWH015
    (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone
    AM251
    1-(2,4-dicholorophenyl)-5-(4-iodophenyl)-4-morphoniyl-1H-pyrazole-3-carboxamide
    SR144528
    5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide
    HU-210
    (−)-11-hydroxyl-Δ8-tetrahydrocannabinol-dimethylheptyl
    CID2745687
    methyl 5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate
    SR141716A
    N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide
    HA
    hemagglutinin
    GFP
    green fluorescent protein
    PCR
    polymerase chain reaction
    PBS
    phosphate-buffered saline
    PTX
    pertussis-toxin
    βarr2
    β-arrestin2
    UGPR35β
    U2OS cells permanently expressing HA-GPR35a and βarr2-GFP
    DHNA
    1,4-dihydroxy-2-naphthoic acid
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene
    CID2745684
    methyl 1-(2,4-difluorophenyl)-5-[(methylcarbamothioylhydrazinylidene)methyl]pyrazole-4-carboxylate
    FDA
    U.S. Food and Drug Administration.

  • Received June 1, 2010.
  • Accepted July 22, 2010.
  • Copyright © 2010 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: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive Activity
(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
Rapid CommunicationAccelerated Communication

Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive Activity

Pingwei Zhao, Haleli Sharir, Ankur Kapur, Alan Cowan, Ellen B. Geller, Martin W. Adler, Herbert H. Seltzman, Patricia H. Reggio, Susanne Heynen-Genel, Michelle Sauer, Thomas D.Y. Chung, Yushi Bai, Wei Chen, Marc G. Caron, Larry S. Barak and Mary E. Abood
Molecular Pharmacology October 1, 2010, 78 (4) 560-568; DOI: https://doi.org/10.1124/mol.110.066746

Citation Manager Formats

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

Share
Rapid CommunicationAccelerated Communication

Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive Activity

Pingwei Zhao, Haleli Sharir, Ankur Kapur, Alan Cowan, Ellen B. Geller, Martin W. Adler, Herbert H. Seltzman, Patricia H. Reggio, Susanne Heynen-Genel, Michelle Sauer, Thomas D.Y. Chung, Yushi Bai, Wei Chen, Marc G. Caron, Larry S. Barak and Mary E. Abood
Molecular Pharmacology October 1, 2010, 78 (4) 560-568; DOI: https://doi.org/10.1124/mol.110.066746
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • GABAA Receptor Desensitization by Low GABA
  • Structure of the Diltiazem Receptor Site on Calcium Channels
  • 5-HT and Sleep
Show more Accelerated Communication

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