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 ArticleBEHAVIORAL PHARMACOLOGY

FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH2): A Peripheral Efficacious κ Opioid Agonist with Unprecedented Selectivity

Todd W. Vanderah, Claudio D. Schteingart, Jerzy Trojnar, Jean-Louis Junien, Josephine Lai and Pierre J.-M. Riviere
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 326-333; DOI: https://doi.org/10.1124/jpet.104.065391
Todd W. Vanderah
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudio D. Schteingart
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jerzy Trojnar
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jean-Louis Junien
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Josephine Lai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pierre J.-M. Riviere
  • 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 side effects typically associated with the clinical profiles of opioid μ-receptor agonists have driven continuing efforts to identify novel efficacious analgesics, including agonists acting at opioid κ receptors. Unfortunately, the therapeutic potential of κ agonists seems limited by significant central nervous system side effects. κ Opioid agonists, however, exhibit potent peripherally mediated antihyperalgesic and antinociceptive effects, suggesting that a peripherally acting κ agonist may be efficacious in pain control with a more desirable safety profile than that associated with currently available opioids. Here, we report an all d-amino acid tetrapeptide characterized as a novel, highly selective κ opioid receptor agonist. FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH2) showed selectivity for the human κ opioid receptor of greater than 30,000- and 68,000-fold versus human μ opioid receptor and human δ-opioid receptor receptors, respectively, and efficacious agonist activity using in vitro tissue assays. FE200041 produced local, peripheral antinociception in the hindpaw ipsilateral, but not contralateral, to injection. Antinociceptive effects of FE200041 in the mouse acetic acid writhing assay lasted over 60 min and were antagonized by naloxone and by selective κ, but not μ, opioid receptor antagonists. FE200041 significantly inhibited acetic acid writhing and inhibited formalin-induced flinching in rats. FE200041 did not elicit sedation or motor impairment after systemic administration at a dose 10-fold higher than that needed to achieve antinociception. FE200041 is thus a potent peripherally restricted opioid κ agonist with no demonstrable side effects typical of κ agonists with central nervous system activity and with unprecedented selectivity for the opioid κ receptor. The pharmacology of this compound suggests the possibility of therapeutic application.

Footnotes

  • These studies were supported by Ferring Research Institute Inc.

  • DOI: 10.1124/jpet.104.065391.

  • ABBREVIATIONS: CNS, central nervous system; GTPγS, guanosine 5′-O-(3-thio)triphosphate; i.paw, injection into the hindpaw; β-FNA, β-funaltrexamine; nor-BNI, nor-binaltorphimine; hKOR, human κ opioid receptor; hMOR, human μ opioid receptor; hDOR, human δ opioid receptor; MVD, mouse vas deferens; CI, confidence interval; FE200041, d-Phe-d-Phe-d-Nle-o-Arg-NH2; ICI 204448, ((±)-[3-[1-[[3,4-dichlorophenyl)acetyl]methylamino]-2-(1-pyrrolindinyl)ethyl]phenoxy]acetic acid hydrochloride; GR 94839, 4-acetyl-1-(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-1-pyrrolidinyl)methyl]piperazine; E-2078, N-methyl-Tyr1,N-methyl-Arg7,d-Leu8dynorphin A[1-8]ethylamide; SK-9709, Tyr-d-Ala-Phe-Leu-Arg Ψ (CH2NH) Arg-NH2; U50,488, (-)3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide; ICI 174,864, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu; U69,593, (5α,7α,8β)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)-benzeneacetamide.

    • Received January 12, 2004.
    • Accepted February 24, 2004.
  • 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: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
  • 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.
FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH2): A Peripheral Efficacious κ Opioid Agonist with Unprecedented Selectivity
(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 ArticleBEHAVIORAL PHARMACOLOGY

FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH2): A Peripheral Efficacious κ Opioid Agonist with Unprecedented Selectivity

Todd W. Vanderah, Claudio D. Schteingart, Jerzy Trojnar, Jean-Louis Junien, Josephine Lai and Pierre J.-M. Riviere
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 326-333; DOI: https://doi.org/10.1124/jpet.104.065391

Citation Manager Formats

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

Share
Research ArticleBEHAVIORAL PHARMACOLOGY

FE200041 (d-Phe-d-Phe-d-Nle-d-Arg-NH2): A Peripheral Efficacious κ Opioid Agonist with Unprecedented Selectivity

Todd W. Vanderah, Claudio D. Schteingart, Jerzy Trojnar, Jean-Louis Junien, Josephine Lai and Pierre J.-M. Riviere
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 326-333; DOI: https://doi.org/10.1124/jpet.104.065391
Reddit logo Twitter logo Facebook 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

  • Ventilatory effects of fentanyl, heroin, and methamphetamine
  • Cromakalim Prodrugs are Analgesics in Chronic Pain Models
  • Chronic Naltrexone: Opioid-Seeking and Antinociception
Show more Behavioral Pharmacology

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