TY - JOUR
T1 - A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor
AU - Chiellini, Grazia
AU - Apriletti, James W.
AU - Yoshihara, Hikari Al
AU - Baxter, John D.
AU - Ribeiro, Ralff C.J.
AU - Scanlan, Thomas S.
N1 - Funding Information:
This work was supported by a grant from the Natlonal Institutes of Health (DK52798) to T.S.S. G.C. was supported in part by a fellowship from the University of Plsa, Italy. T.S.S. is an Alfred P. Sloan Research Fellow. Mass spectral analysis of synthetic compounds was provided by the Mass Spectrometry Facility at UCSF supported by the NIH Division of Research Resources (RR01 614).
PY - 1998/6
Y1 - 1998/6
N2 - 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.
AB - 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.
KW - Biaryl alcohol
KW - Selective alkylation
KW - Subtype selectivity
KW - Thyroid hormone receptor
KW - Thyromimetic
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U2 - 10.1016/S1074-5521(98)90168-5
DO - 10.1016/S1074-5521(98)90168-5
M3 - Article
C2 - 9653548
AN - SCOPUS:0032101890
SN - 1074-5521
VL - 5
SP - 299
EP - 306
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 6
ER -