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 developed a new scheme for the synthesis of dihydroquinazolin-4-ones and quinazoline-4-ones as TSH-R agonists. We then evaluated the properties of these novel compounds. Of note, one of these novel analogs was 80-fold more potent than the parent compound found in a high throughput screen. 2) We showed that a small molecule, drug-like antagonist that we had discovered inhibits the activation of TSH-Rs on orbital fibroblasts obtained from patients with Graves' ophthalmopathy, the eye disease associated with Graves' hyperthyroidism. This is an important finding since it is proof of principle that TSH-Rs on Graves' orbital fibroblasts may be a target with therapy of this aspect of the disease. Of ote, there is at present no benign medical therapy for Graves' ophthalmopathy.