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

Two Novel and Selective Nonimidazole H3 Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization

Gerard B. Fox, Jia Bao Pan, Richard J. Radek, Angela M. Lewis, R. Scott Bitner, Timothy A. Esbenshade, Ramin Faghih, Youssef L. Bennani, Michael Williams, Betty B. Yao, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics June 2003, 305 (3) 897-908; DOI: https://doi.org/10.1124/jpet.102.047241
Gerard B. Fox
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jia Bao Pan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard J. Radek
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Angela M. Lewis
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. Scott Bitner
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy A. Esbenshade
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ramin Faghih
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Youssef L. Bennani
  • 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
Betty B. Yao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael W. Decker
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Arthur A. Hancock
  • 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

Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H3R antagonists are either not selective for H3Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H3R antagonists with improved safety indices. Functional blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an acute dipsogenia response to the selective H3R agonist (R)-α-methylhistamine [(R)-α-MeHA]. Cognitive performance was improved in a five-trial rat pup avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3 mg/kg), with efficacy comparable with previously published observations for reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT-2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H3R antagonists or cognition-enhancing agents.

Footnotes

  • Funded by Abbott Laboratories, Inc. Portions of this work were previously presented at the 31st Annual European Histamine Research Society Meeting, May 22–26, 2002 and at the 32nd Annual Society for Neuroscience Meeting, November 2–7, 2002.

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

  • DOI: 10.1124/jpet.102.047241.

  • ABBREVIATIONS: H3R, H3 receptor; (R)-α-MeHA, (R)-α-methylhistamine; A-304121, (4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy) phenyl)cyclopropylmethanone; A-317920, N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide; ADHD, attention deficit hyperactivity disorder; GT-2331, (1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole; TIs, therapeutic indices; SHR, spontaneously hypertensive rat; RID, ratio of investigation duration; EEG, electroencephalogram; FFT, fast Fourier transform; ANOVA, analysis of variance; ABT-418, (S)-3-methyl-5(1-methyl-2-pyrrolidinyl)-isoxazole.

    • Received November 26, 2002.
    • Accepted February 14, 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: 305 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 3
1 Jun 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.
Two Novel and Selective Nonimidazole H3 Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization
(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

Two Novel and Selective Nonimidazole H3 Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization

Gerard B. Fox, Jia Bao Pan, Richard J. Radek, Angela M. Lewis, R. Scott Bitner, Timothy A. Esbenshade, Ramin Faghih, Youssef L. Bennani, Michael Williams, Betty B. Yao, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 897-908; DOI: https://doi.org/10.1124/jpet.102.047241

Citation Manager Formats

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

Share
Research ArticleNEUROPHARMACOLOGY

Two Novel and Selective Nonimidazole H3 Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization

Gerard B. Fox, Jia Bao Pan, Richard J. Radek, Angela M. Lewis, R. Scott Bitner, Timothy A. Esbenshade, Ramin Faghih, Youssef L. Bennani, Michael Williams, Betty B. Yao, Michael W. Decker and Arthur A. Hancock
Journal of Pharmacology and Experimental Therapeutics June 1, 2003, 305 (3) 897-908; DOI: https://doi.org/10.1124/jpet.102.047241
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

  • Glycine receptor modulation using monoclonal antibodies
  • Iclepertin (BI 425809) in Schizophrenia-Related Models
  • D1 Agonist Versus Methylphenidate on PFC Working Memory
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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics