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This version published online on April 22, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0050
A more recent version of this article appeared on July 1, 2004
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Submitted on February 5, 2004
Accepted on April 16, 2004

Dissecting physiological roles of estrogen receptor {alpha} and {beta} with potent selective ligands from structure-based design

Alexander Hillisch, Olaf Peters, Dirk Kosemund, Gerd Müller, Alexander Walter, Birgitt Schneider, Gudrun Reddersen, Walter Elger, and Karl-Heinrich Fritzemeier*

*EnTec Gesellschaft für Endokrinologische Technologie mbH, Adolf-Reichwein-Str. 20, D-07745 Jena, Germany; Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, D-07745 Jena, Germany; Schering AG, Müllerstr. 170-178, D-13342 Berlin, Germany

* To whom correspondence should be addressed. E-mail: karlheinrich.fritzemeier{at}schering.de.

The distinct roles of the two estrogen receptor isotypes, ER{alpha} and ER{beta}, 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{alpha} and ER{beta} will be provided by the application of isotype selective ER agonists. Based on the crystal structure of the ER{alpha} ligand-binding domain (LBD) and a homology model of the ER{beta}-LBD, 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{alpha} or ER{beta} 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{alpha}- and ER{beta}-selective agonists in comparison to 17{beta}-estradiol. The ER{alpha} agonist induced uterine growth and caused bone-protective effects, reduced LH and FSH plasma levels and increased angiotensin I while the ER{beta} 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{alpha}. Simultaneous administration of the ER{alpha} and ER{beta} ligand did not lead to an attenuation of ER{alpha}-mediated effects on the uterus, pituitary and liver parameters.
Key words: Structure-based drug design • homology model • estrogen receptor {alpha} and {beta} • transactivation assay • in vivo pharmacology

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  GR  |  MR  |  PR  |  AR
Ligands:   17β-Estradiol



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