Estrogen is a critical hormone in the human body that regulates the growth, development and homeostasis of many tissues. Physiological responses to estrogen include the regulation of mammalian reproduction and breast function, central nervous and immune systems, skeletal physiology and vascular function. We have recently described novel functions of the seven transmembrane G protein-coupled estrogen receptor, GPR30. This receptor is activated by both agonists and antagonists of the classical estrogen receptors, ER1 and ER2. Until recently there were no known specific ligands for GPR30, making traditional pharmacological approaches to the study of this receptor difficult. Our recent studies however have combined both virtual and biomolecular screening to discover the first GPR30-selective agonist, G-1.
The specific aims of this application are: 1. Perform a combination of virtual and biomolecular screening to identify additional GPR30-specific ligands based on compounds presently known to bind and activate GPR30. Structure-activity analyses will be carried out to determine the critical molecular determinants for GPR30 binding selectivity and activity as compared to classical estrogen receptors. 2. Based on the biomolecular screening results and structure-activity analyses of Aim 1, rationally design and synthesize small libraries (up to 20 compounds per cycle) of novel G-1-based ligands. The goal of this aim is to separate agonism from antagonism within ligands, and to further evaluate the SAR of novel GPR30 ligands through targeted synthetic chemistry. 3. Characterize the biological functions of the compounds identified and synthesized in Aims 1 and 2. A collection of functional bioassays will be employed to characterize the biological effects of the compounds displaying activity. These assays will include intracellular signaling assays such as calcium mobilization, ERK and EGFR phosphorylation and PI3K activation;more complex cellular assays such as transcriptional activation, cell migration and proliferation;and in vivo studies using mouse models. Understanding the pharmacological profile and structure-activity relationships for ligand binding to GPR30 will be critical to the discovery of novel drugs that target this receptor for the purposes of revealing the underlying physiology of the receptor and developing therapeutic approaches for the improved treatment of estrogen-dependent cancers.

Public Health Relevance

Estrogen plays an important role in normal and disease biology. We have characterized a novel membrane estrogen receptor that likely plays a role in estrogen biology. The goal of this work is to develop novel compounds that can specifically target this new receptor to either activate or inhibit its activity without affecting other estrogen receptors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Lees, Robert G
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University of New Mexico
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Barton, Matthias; Prossnitz, Eric R (2017) Rapid vasodilation to raloxifene: role of oestrogen receptors and off-target effects. Br J Pharmacol 174:4201-4202
Meyer, Matthias R; Rosemann, Thomas; Barton, Matthias et al. (2017) GPER Mediates Functional Endothelial Aging in Renal Arteries. Pharmacology 100:188-193
Meyer, Matthias R; Fredette, Natalie C; Sharma, Geetanjali et al. (2016) GPER is required for the age-dependent upregulation of the myocardial endothelin system. Life Sci 159:61-65
Meyer, Matthias R; Fredette, Natalie C; Daniel, Christoph et al. (2016) Obligatory role for GPER in cardiovascular aging and disease. Sci Signal 9:ra105
Sharma, Geetanjali; Prossnitz, Eric R (2016) GPER/GPR30 Knockout Mice: Effects of GPER on Metabolism. Methods Mol Biol 1366:489-502
Prossnitz, Eric R; Arterburn, Jeffrey B (2015) International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators. Pharmacol Rev 67:505-40
Meyer, Matthias R; Fredette, Natalie C; Barton, Matthias et al. (2015) Prostanoid-mediated contractions of the carotid artery become Nox2-independent with aging. Age (Dordr) 37:9806
Meyer, Matthias R; Fredette, Natalie C; Barton, Matthias et al. (2015) G protein-coupled estrogen receptor inhibits vascular prostanoid production and activity. J Endocrinol 227:61-9
Barton, Matthias; Prossnitz, Eric R (2015) Emerging roles of GPER in diabetes and atherosclerosis. Trends Endocrinol Metab 26:185-92
Prossnitz, Eric R; Hathaway, Helen J (2015) What have we learned about GPER function in physiology and disease from knockout mice? J Steroid Biochem Mol Biol 153:114-26

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