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

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

Rita Raddatz, Robert L. Hudkins, Joanne R. Mathiasen, John A. Gruner, Dorothy G. Flood, Lisa D. Aimone, Siyuan Le, Hervé Schaffhauser, Emir Duzic, Maciej Gasior, Donna Bozyczko-Coyne, Michael J. Marino, Mark A. Ator, Edward R. Bacon, John P. Mallamo and Michael Williams
Journal of Pharmacology and Experimental Therapeutics January 2012, 340 (1) 124-133; DOI: https://doi.org/10.1124/jpet.111.186585
Rita Raddatz
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert L. Hudkins
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joanne R. Mathiasen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John A. Gruner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dorothy G. Flood
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa D. Aimone
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Siyuan Le
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hervé Schaffhauser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emir Duzic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maciej Gasior
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donna Bozyczko-Coyne
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael J. Marino
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark A. Ator
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edward R. Bacon
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John P. Mallamo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Williams
  • 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

CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H3 receptor (H3R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki = 2.7 ± 0.3 nM) and recombinant rat and human H3R-expressing systems (Ki = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [35S]guanosine 5′-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H3R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC50 = 0.1 ± 0.003 mg/kg), and antagonism of the H3R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.186585.

  • ABBREVIATIONS:

    CNS
    central nervous system
    H3R
    histamine H3 receptor
    rH3R
    rat H3R
    hH3R
    human H3R
    CEP-26401
    6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl
    ABT-239
    4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile (L) tartrate
    RAMH
    R-α-methylhistamine
    GTPγS
    guanosine 5′-O-(γ-thio)triphosphate
    CHO
    Chinese hamster ovary
    PPI
    prepulse inhibition
    [3H]NAMH
    [3H]N-α-methylhistamine
    RID
    ratio of investigation duration
    DTT
    dithiothreitol
    EEG
    electroencephalographic
    EMG
    electromyographic
    SWS
    slow wave sleep
    REM
    rapid eye movement
    REMS
    REM sleep
    OCC50
    50% occupancy
    ANOVA
    analysis of variance
    DMSO
    dimethyl sulfoxide
    FBS
    fetal bovine serum
    PEG400
    polyethylene glycol 400
    ACh
    acetylcholine
    BSA
    bovine serum albumin
    IEI
    interexposure interval
    GSK189254
    6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide
    PF-03654746
    (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide
    MK-0249
    2-methyl-3-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-trifluoromethyl-3H-quinazolin-4-one
    JNJ-31001074
    1-(4-cyclopropylpiperazin-1-yl)-1-[4-morpholin-4-ylmethyl)phenyl] methanone.

  • Received August 2, 2011.
  • Accepted October 13, 2011.
  • Copyright © 2012 by 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: 340 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 1
1 Jan 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 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.
CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
(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

H3 Receptor Antagonist CEP-26401

Rita Raddatz, Robert L. Hudkins, Joanne R. Mathiasen, John A. Gruner, Dorothy G. Flood, Lisa D. Aimone, Siyuan Le, Hervé Schaffhauser, Emir Duzic, Maciej Gasior, Donna Bozyczko-Coyne, Michael J. Marino, Mark A. Ator, Edward R. Bacon, John P. Mallamo and Michael Williams
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 124-133; DOI: https://doi.org/10.1124/jpet.111.186585

Citation Manager Formats

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

Share
Research ArticleNeuropharmacology

H3 Receptor Antagonist CEP-26401

Rita Raddatz, Robert L. Hudkins, Joanne R. Mathiasen, John A. Gruner, Dorothy G. Flood, Lisa D. Aimone, Siyuan Le, Hervé Schaffhauser, Emir Duzic, Maciej Gasior, Donna Bozyczko-Coyne, Michael J. Marino, Mark A. Ator, Edward R. Bacon, John P. Mallamo and Michael Williams
Journal of Pharmacology and Experimental Therapeutics January 1, 2012, 340 (1) 124-133; DOI: https://doi.org/10.1124/jpet.111.186585
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

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

Related Articles

Cited By...

More in this TOC Section

  • KRM-II-81 Analogs
  • Substituted Tryptamine Activity at 5-HT Receptors and SERT
  • VTA muscarinic M5 receptors and effort-choice behavior
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