Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, discovery of probes/drugs for 7TMRs is an important goal of biomedical research. We have begun our research using high throughput screening (HTS) for low molecular weight (LMW) ligands for 7TMRs with the receptor for thyroid-stimulating hormone (TSH-R). During this year, we employed a cell-based assay that we developed for activation of TSH-R by LMW agonists and a complementary assay for LMW inhibitors of TSH stimulation of TSH-R for HTS. We identified new agonists for TSH-R that show excellent selectivity because they do not activate the closely related receptors for luteinizing hormone or follicle-stimulating hormone. These are the first LMW agonists for TSH-R reported. We continue to modify these compounds chemically to improve their selectivities, affinities and efficacies. We also identified the first LMW antagonist for TSH-R. Of particular note, is our observation that this antagonist not only inhibits stimulation of TSH-R by TSH but also by thyroid-stimulating antibodies (TsAbs) from patients with Gravess hyperthyroidism.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2008
Total Cost
$301,723
Indirect Cost
City
State
Country
United States
Zip Code
Neumann, S; Place, R F; Krieger, C C et al. (2015) Future Prospects for the Treatment of Graves' Hyperthyroidism and Eye Disease. Horm Metab Res 47:789-96
Gershengorn, Marvin C; Neumann, Susanne (2012) Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 97:4287-92
Neumann, Susanne; Raaka, Bruce M; Gershengorn, Marvin C (2009) Human TSH receptor ligands as pharmacological probes with potential clinical application. Expert Rev Endocrinol Metab 4:669
Moore, Susanna; Jaeschke, Holger; Kleinau, Gunnar et al. (2006) Evaluation of small-molecule modulators of the luteinizing hormone/choriogonadotropin and thyroid stimulating hormone receptors: structure-activity relationships and selective binding patterns. J Med Chem 49:3888-96
Jaschke, Holger; Neumann, Susanne; Moore, Susanna et al. (2006) A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem 281:9841-4