Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice.

Paradigms and Technologies
Therapeutic Approaches


Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.


Neumann, Susanne; Huang, Wenwei; Titus, Steve; Krause, Gerd; Kleinau, Gunnar; Alberobello, Anna Teresa; Zheng, Wei; Southall, Noel; Inglese, James; Austin, Christopher; Celi, Francesco S; Gavrilova, Oksana; Thomas, Craig; Raaka, Bruce M; Gershengorn, Marvin C;


  • Acetamides/ chemical synthesis
  • Acetamides/ chemistry
  • Acetamides/ pharmacology
  • Animals
  • Binding Sites
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP/ metabolism
  • Female
  • Gene Expression/ drug effects
  • Humans
  • Iodide Peroxidase/ genetics
  • Iodide Peroxidase/ metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Structure
  • Organic Chemicals/ chemical synthesis
  • Organic Chemicals/ chemistry
  • Organic Chemicals/ pharmacology
  • Protein Structure, Tertiary
  • Quinazolinones/ chemical synthesis
  • Quinazolinones/ chemistry
  • Quinazolinones/ pharmacology
  • Receptors, Thyrotropin/ agonists
  • Receptors, Thyrotropin/ genetics
  • Receptors, Thyrotropin/ metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroglobulin/ genetics
  • Thyroglobulin/ metabolism
  • Thyroid Gland/ cytology
  • Thyroid Gland/ drug effects
  • Thyroid Gland/ physiology
  • Thyrotropin/ pharmacology
  • Transfection

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