title: A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.
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, TR alpha and TR beta, 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 TR beta over TR alpha. 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 TR beta 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chiellini
authors.forename: J W
authors.initials: JW
authors.lastname: Apriletti
authors.forename: H A
authors.initials: HA
authors.lastname: Yoshihara
authors.forename: J D
authors.initials: JD
authors.lastname: Baxter
authors.forename: R C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: T S
authors.initials: TS
authors.lastname: Scanlan
mesh_terms: D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D010636:Phenols; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000819:agonists / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine