A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor

Grazia Chiellini, James W. Apriletti, Hikari Al Yoshihara, John D. Baxter, Ralff C J Ribeiro, Thomas (Tom) Scanlan

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Abstract

Background: Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TRα and TRβ, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. Results: We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TRβ over TRα. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. Conclusions: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TRβ selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms.

Original languageEnglish (US)
Pages (from-to)299-306
Number of pages8
JournalChemistry and Biology
Volume5
Issue number6
Publication statusPublished - Jun 1998
Externally publishedYes

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Keywords

  • Biaryl alcohol
  • Selective alkylation
  • Subtype selectivity
  • Thyroid hormone receptor
  • Thyromimetic

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Chiellini, G., Apriletti, J. W., Yoshihara, H. A., Baxter, J. D., Ribeiro, R. C. J., & Scanlan, T. T. (1998). A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chemistry and Biology, 5(6), 299-306.