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 ArticleDrug Discovery and Translational Medicine

Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder

Pascal Bonaventure, Christine Dugovic, Michelle Kramer, Peter De Boer, Jaskaran Singh, Sue Wilson, Kirk Bertelsen, Jianing Di, Jonathan Shelton, Leah Aluisio, Lisa Dvorak, Ian Fraser, Brian Lord, Diane Nepomuceno, Abdellah Ahnaou, Wilhelmus Drinkenburg, Wenying Chai, Curt Dvorak, Steve Sands, Nicholas Carruthers and Timothy W. Lovenberg
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 429-440; DOI: https://doi.org/10.1124/jpet.112.193995
Pascal Bonaventure
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christine Dugovic
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Kramer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter De Boer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jaskaran Singh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sue Wilson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kirk Bertelsen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jianing Di
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan Shelton
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Leah Aluisio
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Dvorak
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ian Fraser
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Brian Lord
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Diane Nepomuceno
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Abdellah Ahnaou
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wilhelmus Drinkenburg
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wenying Chai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Curt Dvorak
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steve Sands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas Carruthers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy W. Lovenberg
  • 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

In rodents 5-hydroxytryptamine type 7 (5-HT7) receptor blockade has been shown to be effective in models of depression and to increase the latency to rapid eye movement (REM) sleep and decrease REM duration. In the clinic, the REM sleep reduction observed with many antidepressants may serve as a biomarker. We report here the preclinical and clinical evaluation of a 5-HT7 receptor antagonist, (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate) (JNJ-18038683). In rodents, JNJ-18038683 increased the latency to REM sleep and decreased REM duration, and this effect was maintained after repeated administration for 7 days. The compound was effective in the mouse tail suspension test. JNJ-18038683 enhanced serotonin transmission, antidepressant-like behavior, and REM sleep suppression induced by citalopram in rodents. In healthy human volunteers JNJ-18038683 prolonged REM latency and reduced REM sleep duration, demonstrating that the effect of 5-HT7 blockade on REM sleep translated from rodents to humans. Like in rats, JNJ-18038683 enhanced REM sleep suppression induced by citalopram in humans, although a drug-drug interaction could not be ruled out. In a double-blind, active, and placebo-controlled clinical trial in 225 patients suffering from major depressive disorder, neither treatment with pharmacologically active doses of JNJ-18038683 or escitalopram separated from placebo, indicating a failed study lacking assay sensitivity. Post hoc analyses using an enrichment window strategy, where all the efficacy data from sites with an implausible high placebo response [placebo group Montgomery-Åsberg Depression Rating Scale (MADRS) < = 12] and from sites with no placebo response (MADRS > = 28) are removed, there was a clinically meaningful difference between JNJ-18038683 and placebo. Further clinical studies are required to characterize the potential antidepressant efficacy of JNJ-18038683.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.112.193995.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    5-HT
    5-hydroxytryptamine (serotonin)
    h5-HT
    human 5-HT
    5-CT
    5-carboxamidotryptamine
    ANOVA
    analysis of variance
    ASEX
    Arizona Sexual Experience Scale
    AUC
    area under the curve
    DOI
    (±)-2,5-dimethoxy-4-iodoamphetamine
    EEG
    electroencephalogram
    EMG
    electromyogram
    FLIPR
    fluorescence imaging plate reader
    HAMD
    Hamilton Rating Scale for Depression
    HEK
    human embryonic kidney
    JNJ-18038683
    (3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1-(phenylmethyl)pyrazolo[3,4-d]azepine 2-hydroxy-1,2,3-propanetricarboxylate)
    MADRS
    Montgomery-Åsberg Depression Rating Scale
    MDD
    major depressive disorder
    PSG
    polysomnogram
    REM
    rapid eye movement
    NREM
    non-REM sleep
    RO-4368554
    3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole
    SB-269970
    (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine
    SSRI
    selective serotonin reuptake inhibitor.

  • Received March 5, 2012.
  • Accepted May 7, 2012.
  • 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: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 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.
Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder
(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 ArticleDrug Discovery and Translational Medicine

Translational Evaluation of a 5-HT7 Receptor Antagonist

Pascal Bonaventure, Christine Dugovic, Michelle Kramer, Peter De Boer, Jaskaran Singh, Sue Wilson, Kirk Bertelsen, Jianing Di, Jonathan Shelton, Leah Aluisio, Lisa Dvorak, Ian Fraser, Brian Lord, Diane Nepomuceno, Abdellah Ahnaou, Wilhelmus Drinkenburg, Wenying Chai, Curt Dvorak, Steve Sands, Nicholas Carruthers and Timothy W. Lovenberg
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 429-440; DOI: https://doi.org/10.1124/jpet.112.193995

Citation Manager Formats

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

Share
Research ArticleDrug Discovery and Translational Medicine

Translational Evaluation of a 5-HT7 Receptor Antagonist

Pascal Bonaventure, Christine Dugovic, Michelle Kramer, Peter De Boer, Jaskaran Singh, Sue Wilson, Kirk Bertelsen, Jianing Di, Jonathan Shelton, Leah Aluisio, Lisa Dvorak, Ian Fraser, Brian Lord, Diane Nepomuceno, Abdellah Ahnaou, Wilhelmus Drinkenburg, Wenying Chai, Curt Dvorak, Steve Sands, Nicholas Carruthers and Timothy W. Lovenberg
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 429-440; DOI: https://doi.org/10.1124/jpet.112.193995
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
    • 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

  • Glucose transport modulators and mouse behavioral testing
  • Translational PK/PD Modeling of M3258
  • Kidney protective effects of BI 685509
Show more Drug Discovery and Translational Medicine

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