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Dissecting Physiological Roles of Estrogen Receptor and ß with Potent Selective Ligands from Structure-Based Design

EnTec Gesellschaft für Endokrinologische Technologie GmbH (A.H., B.S., G.R., W.E.), and Jenapharm GmbH & Co. KG (O.P., D.K., G.M.), D-07745 Jena, Germany; and Schering AG (A.W., K.-H.F.), D-13342 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Karl-Heinrich Fritzemeier, Schering AG, Müllerstrasse 170–178, D-13342 Berlin, Germany. E-mail: karlheinrich.fritzemeier{at}schering.de.

The distinct roles of the two estrogen receptor (ER) isotypes, ER and ERß, in mediating the physiological responses to estrogens are not completely understood. Although knockout animal experiments have been aiding to gain insight into estrogen signaling, additional information on the function of ER and ERß will be provided by the application of isotype-selective ER agonists. Based on the crystal structure of the ER ligand binding domain and a homology model of the ERß-ligand binding domain, we have designed steroidal ligands that exploit the differences in size and flexibility of the two ligand binding cavities. Compounds predicted to bind preferentially to either ER or ERß were synthesized and tested in vitro using radio-ligand competition and transactivation assays. This approach directly led to highly ER isotype-selective (200-fold) and potent ligands. To unravel physiological roles of the two receptors, in vivo experiments with rats were conducted using the ER- and ERß-selective agonists in comparison to 17ß-estradiol. The ER agonist induced uterine growth, caused bone-protective effects, reduced LH and FSH plasma levels, and increased angiotensin I, whereas the ERß agonist did not at all or only at high doses lead to such effects, despite high plasma levels. It can thus be concluded that estrogen effects on the uterus, pituitary, bone, and liver are primarily mediated via ER. Simultaneous administration of the ER and ERß ligand did not lead to an attenuation of ER-mediated effects on the uterus, pituitary, and liver parameters.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  GR  |  MR  |  PR  |  AR

Ligands:   17β-Estradiol