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

High-Affinity Partial Agonists of the Vanilloid Receptor

Yun Wang, Attila Toth, Richard Tran, Tamas Szabo, Jacqueline D. Welter, Peter M. Blumberg, Jiyoun Lee, Sang-Uk Kang, Ju-Ok Lim and Jeewoo Lee
Molecular Pharmacology August 2003, 64 (2) 325-333; DOI: https://doi.org/10.1124/mol.64.2.325
Yun Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Attila Toth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard Tran
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tamas Szabo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jacqueline D. Welter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter M. Blumberg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jiyoun Lee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sang-Uk Kang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ju-Ok Lim
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeewoo Lee
  • 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

The vanilloid receptor VR1 is a polymodal nociceptor sensitive to capsaicin, protons, and heat. Because VR1 represents an attractive therapeutic target for conditions ranging from long-term pain to bladder hyperreflexia, we and other groups have sought to develop novel ligands with enhanced potencies and novel pharmacological properties. Here, we characterize two compounds, N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea (JYL827) and N-(4-tert-butylbenzyl)-N′-[3-methoxy-4-(methylsulfonylamino)benzyl]thiourea (JYL1511), that function as partial agonists for rat VR1 heterologously expressed in Chinese hamster ovary cells. Both compounds showed substantially enhanced potency, inhibiting [3H] resiniferatoxin binding with Ki values of 29.3 ± 7.6 and 50.4 ± 16.5 nM, respectively, compared with 1810 ± 270 nM for capsaicin. The compounds showed different extents of partial agonism, 6.8 ± 0.7% and 17.4 ± 0.6%, respectively, and the expected corresponding degrees of partial antagonism (93.9 ± 0.9 and 84.1 ± 3.2%, respectively). Their IC50 values for antagonism of 45Ca2+ uptake in response to capsaicin were 67.3 ± 24.9 nM and 3.4 ± 0.5 nM, respectively. Protons, temperature, and protein kinase C all function as coactivators/modulators of rVR1. All enhanced the extent of partial agonism of JYL827 and JYL1511. Thus, at pH 5.5, for example, the extents of partial agonism increased to 54.9 ± 2.5% and to 90.7 ± 1.7%, respectively, relative to the response elicited by 300 nM capsaicin. The extents of partial antagonism decreased correspondingly. Compounds such as JYL827 and JYL1511 now permit exploration of the potential utility of partial agonists of rVR1 in animal models. Our results emphasize, moreover, the strong dependence of such partial agonists on other modulators of rVR1 and predict that their biological behavior will depend strongly on biological context.

  • Received December 24, 2002.
  • Accepted April 10, 2003.
  • 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: 64 (2)
Molecular Pharmacology
Vol. 64, Issue 2
1 Aug 2003
  • Table of Contents
  • About the Cover
  • Index by author
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.
High-Affinity Partial Agonists of the Vanilloid Receptor
(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

High-Affinity Partial Agonists of the Vanilloid Receptor

Yun Wang, Attila Toth, Richard Tran, Tamas Szabo, Jacqueline D. Welter, Peter M. Blumberg, Jiyoun Lee, Sang-Uk Kang, Ju-Ok Lim and Jeewoo Lee
Molecular Pharmacology August 1, 2003, 64 (2) 325-333; DOI: https://doi.org/10.1124/mol.64.2.325

Citation Manager Formats

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

Share
Research ArticleArticle

High-Affinity Partial Agonists of the Vanilloid Receptor

Yun Wang, Attila Toth, Richard Tran, Tamas Szabo, Jacqueline D. Welter, Peter M. Blumberg, Jiyoun Lee, Sang-Uk Kang, Ju-Ok Lim and Jeewoo Lee
Molecular Pharmacology August 1, 2003, 64 (2) 325-333; DOI: https://doi.org/10.1124/mol.64.2.325
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
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Therapeutic Effects of FGF23 Antagonists in Hyp Mice
  • TRPV3 and TRPV4 Channels Coassemble into Heterotetramers
  • Secretin Amino-Terminal Structure-Activity Relationships and Complementary Mutagenesis at the Site of Docking to the Secretin Receptor
Show more Article

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