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
Journal of Pharmacology and Experimental Therapeutics
  • 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
Journal of Pharmacology and Experimental Therapeutics

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 jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNEUROPHARMACOLOGY

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Kenneth J. Valenzano, Elfrida R. Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Qun Sun, Yakov Rotshteyn, Joseph Francis, James Limberis, Shiazah Malik, Edward R. Whittemore and Dianne Hodges
Journal of Pharmacology and Experimental Therapeutics July 2003, 306 (1) 377-386; DOI: https://doi.org/10.1124/jpet.102.045674
Kenneth J. Valenzano
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elfrida R. Grant
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gang Wu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohamed Hachicha
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lori Schmid
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laykea Tafesse
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Qun Sun
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yakov Rotshteyn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph Francis
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James Limberis
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shiazah Malik
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edward R. Whittemore
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dianne Hodges
  • 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

Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.

Footnotes

  • DOI: 10.1124/jpet.102.045674.

  • ABBREVIATIONS: CNS, central nervous system; VR1, vanilloid receptor 1; BCTC, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide; RT, reverse transcription; PCR, polymerase chain reaction; HEK, human embryonic kidney; FLIPR, fluorescent imaging plate reader; SIF, synthetic interstitial fluid; GTPγS, guanosine 5′-O-(3-thio)triphosphate; ASIC, acid-sensing ion channel.

  • ↵1 Current address: Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612.

  • ↵2 Current address: Pharmacia Corporation, 4901 Searle Pkwy., Skokie, IL 60077.

  • ↵3 Current address: Vertex Pharmaceuticals LLC, 11010 Torreyana Rd., San Diego, CA 92121.

    • Received January 3, 2003.
    • Accepted April 15, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET 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

Journal of Pharmacology and Experimental Therapeutics: 306 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 1
1 Jul 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 Journal of Pharmacology and Experimental Therapeutics 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.
N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNEUROPHARMACOLOGY

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Kenneth J. Valenzano, Elfrida R. Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Qun Sun, Yakov Rotshteyn, Joseph Francis, James Limberis, Shiazah Malik, Edward R. Whittemore and Dianne Hodges
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 377-386; DOI: https://doi.org/10.1124/jpet.102.045674

Citation Manager Formats

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

Share
Research ArticleNEUROPHARMACOLOGY

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Kenneth J. Valenzano, Elfrida R. Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Qun Sun, Yakov Rotshteyn, Joseph Francis, James Limberis, Shiazah Malik, Edward R. Whittemore and Dianne Hodges
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 377-386; DOI: https://doi.org/10.1124/jpet.102.045674
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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Substituted tryptamine activity at 5-HT receptors & SERT
  • In Vivo SRI-32743 Attenuates Tat Effects on Extracellular DA
  • Kv7 Opener Attenuates Seizures and Cognitive Deficit
Show more Neuropharmacology

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 JPET
  • 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
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics