High Throughput Screening for Ligands for Seven Transmembrane-spanning Receptors

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

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 use high throughput screening (HTS) for small molecule ligands (SMLs) for 7TMRs with the receptors for thyroid-stimulating hormone (TSH-R) and thyrotropin-releasing hormone (TRH-R). During this year, we continued our development of these SMLs. 1) We showed that a newly developed analog of one of our SML TSHR antagonists was the first drug of this kind to be effective in an animal model. Specifically, we showed that our new antagonist inhibits thyroid function in mice that are models of endogenous TSH-mediated hyperthyroidism and of thyroid-stimulating antibody-mediated hyperthyroidism, which is a model of Graves' disease (GD) the most common form of hyperthyroidism in humans. 2) Until recently, it was thought that the cells in the soft tissue of the eyes of patients with Graves' ophthalmopathy (GO), a component of GD for which there is no medical therapy, was caused by autoimmune antibody stimulation of fat cells (adipocytes) and not of adipocyte precursor cells. We used a highly sensitive assay we developed to show that precursor cells obtained from the orbital tissue of patients with GO were involved in the pathogenesis of GO by secreting large amounts of hyaluronan, a component of the extracellular matrix and a major component of GO pathology. Moreover, we used a SML antagonist for the TSH-R in cells to show that TSHRs on these cells could be inhibited and lead to marked reduction in the amount of hyaluronan preoduced.. This is further proof that a drug to treat the ophthalmopathy of Graves' disease in humans may be developed.