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 previously reported on a SML agonist for TSH-R that could be used in an animal model to stimulate an increase in radioactive iodine uptake by the thyroid gland and in thyroid hormone secretion after oral administration. We had recognized that the SML was a racemic mixture of two enantiomers. We now have shown that the two enantiomers can be separated and that they exhibit different potencies in vitro and, more importantly, that one is far more effective than the other in vivo. We are currently following up on this observation to increase the bioavailability of the more active enantiomer. 2) We previously reported that a G protein-independent pathway, which uses beta-arrestin-1 as a signal transduction molecule, was important in the signaling by the TSH-R in bone precursor cells. We have now completed a high-throughput screen (in collaboration with NCATS) for SMLs that activate the TSH-R via a beta-arrestin-1 dependent, G protein-independent mechanism and found several lead compounds. We are currently working with chemists at NCATS to improve the pharmacological characteristics of these lead compounds. We think these compounds may be lead drugs for the treatment of osteoporosis in humans.
| Morgan, Sarah J; Neumann, Susanne; Gershengorn, Marvin C (2018) Normal Human Thyrocytes in Culture. Methods Mol Biol 1817:1-7 |
| Dougherty, John P; Wolff, Brian S; Cullen, Mary J et al. (2017) Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. Pharmacol Res 124:1-8 |
| Neumann, Susanne; Padia, Umesh; Cullen, Mary Jane et al. (2016) An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties. Front Endocrinol (Lausanne) 7:105 |
| Dougherty, John P; Springer, Danielle A; Gershengorn, Marvin C (2016) The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse. J Vis Exp : |
| Krieger, Christine C; Place, Robert F; Bevilacqua, Carmine et al. (2016) TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis. J Clin Endocrinol Metab 101:2340-7 |
| Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C (2016) Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. Endocrinology 157:2173-81 |
| Krieger, Christine C; Neumann, Susanne; Place, Robert F et al. (2015) Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves' disease immunoglobins. J Clin Endocrinol Metab 100:1071-7 |
| Boutin, Alisa; Eliseeva, Elena; Gershengorn, Marvin C et al. (2014) ?-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J 28:3446-55 |
| Turcu, Adina F; Kumar, Seema; Neumann, Susanne et al. (2013) A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 98:2153-9 |
| Geras-Raaka, Elizabeth; Neumann, Susanne; Gershengorn, Marvin C (2013) Persistent cAMP Signaling by TSH Receptors Revealed by Phosphodiesterase Inhibition. Thyroid : |
Showing the most recent 10 out of 17 publications
