title: Small molecule TSHR agonists and antagonists.
abstract: TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential.
authors.affiliation: National Institutes of Health, NIDDK, CEB, Receptor and Hormone Action Section, MD 20892, Bethesda, USA. susannen@intra.niddk.nih.gov
authors.forename: S
authors.initials: S
authors.lastname: Neumann
authors.forename: M C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006111:Graves Disease / Q000188:drug therapy*; D006801:Humans; D007456:Iodine Isotopes / Q000378:metabolism; D008024:Ligands; D051379:Mice; D011989:Receptors, Thyrotropin / Q000819:agonists* / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D013974:Thyroxine / Q000097:blood
chemical_list: D007456:Iodine Isotopes; D008024:Ligands; D011989:Receptors, Thyrotropin; D054852:Small Molecule Libraries; D013974:Thyroxine