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
Molecular Pharmacology
  • 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
Molecular Pharmacology

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 molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators

Yuka Inaba, Keiko Yamamoto, Nobuko Yoshimoto, Manabu Matsunawa, Shigeyuki Uno, Sachiko Yamada and Makoto Makishima
Molecular Pharmacology May 2007, 71 (5) 1298-1311; DOI: https://doi.org/10.1124/mol.106.032318
Yuka Inaba
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keiko Yamamoto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nobuko Yoshimoto
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Manabu Matsunawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shigeyuki Uno
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sachiko Yamada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Makoto Makishima
  • 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 vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)2D3 derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)2D3. The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)2D3. It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)2D3, whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D3 derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application.

Footnotes

  • This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (M.M.), and the Ministry of Health, Labor, and Welfare, Japan (M.M.).

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

  • doi:10.1124/mol.106.032318.

  • ABBREVIATIONS: VDR, vitamin D receptor; AF2, activation function 2; H, helix; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; RXR, retinoid X receptor; ER6, everted repeat 6; LBD, ligand-binding domain; MR, mineralocorticoids; HEK, human embryonic kidney; FBS, fetal bovine serum; GST, glutathione transferase; LCA, lithocholic acid; PCR, polymerase chain reaction; ZK159222, (24R)-25-(butoxycarbonyl)-1α,24-dihydroxy-26,27-cyclo-22,23-didehydrovitamin D3; ZK191732, (24R)-1α,24-dihydroxy-25-(4-methylthiazol-2-yl)-26,27-cyclo-22,23-didehydrovitamin D3; ZK16289, (24R)-1α,24-dihydroxy-25-(1-oxohex-1-yl)-26,27-cyclo-22,23-didehydrovitamin D3; ZK168281, (24R)-1α,24-dihydroxy-25-(ethoxyacrylo-3-yl)-26,27-cyclo-22,23-didehydrovitamin D3; TEI-9647, (23S)-1α-hydroxy-25,27-didehydrovitamin D3-26,23-lactone.

    • Received October 31, 2006.
    • Accepted February 21, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm 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

Molecular Pharmacology: 71 (5)
Molecular Pharmacology
Vol. 71, Issue 5
1 May 2007
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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 Molecular Pharmacology 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.
Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators

Yuka Inaba, Keiko Yamamoto, Nobuko Yoshimoto, Manabu Matsunawa, Shigeyuki Uno, Sachiko Yamada and Makoto Makishima
Molecular Pharmacology May 1, 2007, 71 (5) 1298-1311; DOI: https://doi.org/10.1124/mol.106.032318

Citation Manager Formats

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

Share
Research ArticleArticle

Vitamin D3 Derivatives with Adamantane or Lactone Ring Side Chains are Cell Type-Selective Vitamin D Receptor Modulators

Yuka Inaba, Keiko Yamamoto, Nobuko Yoshimoto, Manabu Matsunawa, Shigeyuki Uno, Sachiko Yamada and Makoto Makishima
Molecular Pharmacology May 1, 2007, 71 (5) 1298-1311; DOI: https://doi.org/10.1124/mol.106.032318
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

  • Analgesic Effects and Mechanisms of Licochalcones
  • Induced Fit Ligand Binding to CYP3A4
  • Englerin A Inhibits T-Type Channels
Show more Articles

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 Molecular Pharmacology
  • 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
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

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