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Identification and characterization of steroid receptor ligands

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/10868

Identification and characterization of steroid receptor ligands

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dc.contributor.author Dennis, Megan
dc.date.accessioned 2010-06-25T22:20:23Z
dc.date.available 2010-06-25T22:20:23Z
dc.date.issued 2010-06-25T22:20:23Z
dc.date.submitted May 2010
dc.identifier.uri http://hdl.handle.net/1928/10868
dc.description.abstract This work focuses on steroid receptors, including the androgen receptor (AR), the estrogen receptors (ERs) ERα and ERβ, known as the classical ERs, and GPR30, a recently described G protein-coupled estrogen receptor. Each of these receptors plays a role in many normal tissues and disease pathologies and signaling through steroid receptors is required for growth of many cancers. Additionally, many tissues express more than one estrogen receptor, making delineation of the functions of individual receptors difficult. We have previously identified a GPR30-selective agonist, G-1, and this small molecule has been shown to mediate GPR30 function in a range of in vitro and in vivo systems. Thus, selective mediators of steroid receptor function do exist and will be useful in characterizing receptor function and in investigating therapeutic potential of each receptor individually. We hypothesize that the identification of novel estrogen and androgen receptor ligands will result in further elucidation of steroid receptor function in complex systems. To address the possibility that additional selective ligands for steroid receptors exist, we first optimized a series of AR assays for investigation of a library of small molecules to search for novel AR-mediating functions. Subsequently, high-throughput screening was used to search for selective estrogen receptor ligands and this search identified a small molecule antagonist of GPR30, G15. Follow-up characterization of G15 as well as synthetic chemistry based on the structural similarities resulted in a second-generation GPR30 antagonist, G36, which has increased specificity for GPR30 versus ERα/ERβ. These compounds were used to probe the function of GPR30 in glioma and we find that GPR30 is the functionally important estrogen receptor in this system, regulating the response of glioma cells to both estrogen and tamoxifen. Finally, two series of GPR30-targeted in vivo imaging agents were generated and characterized for biological activity prior to small animal imaging. This work demonstrates the necessary processes involved for small molecule discovery and characterization, as well as several applications for receptor-specific small molecules beyond their initial identification. en_US
dc.language.iso en_US en_US
dc.subject Estrogen en_US
dc.subject Androgen en_US
dc.subject GPR30 en_US
dc.subject GPER en_US
dc.subject Small molecule discovery en_US
dc.subject High throughput screening en_US
dc.subject.lcsh Steroid hormones--Receptors--Analysis.
dc.subject.lcsh Ligands (Biochemistry)--Analysis.
dc.title Identification and characterization of steroid receptor ligands en_US
dc.type Dissertation en_US
dc.description.degree Biomedical Sciences en_US
dc.description.level Doctoral en_US
dc.description.department University of New Mexico. Biomedical Sciences Graduate Program en_US
dc.description.advisor Prossnitz, Eric
dc.description.committee-member Sklar, Larry
dc.description.committee-member Thompson, Todd
dc.description.committee-member Hathaway, Helen


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