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First published on May 5, 2006; DOI: 10.1124/mol.105.021931

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Received for publication December 22, 2005.
Revised April 9, 2006.
Accepted for publication April 14, 2006.

TAMOXIFEN AND RALOXIFENE DIFFER IN THEIR FUNCTIONAL INTERACTIONS WITH ASPARTATE 351 OF ESTROGEN RECEPTOR ALPHA

Guila Dayan 1, Mathieu Lupien 1, Anick Auger 1, Silvia I Anghel 1, Walter Rocha 1, Sebastien Croisetiere 1, John A. Katzenellenbogen 2, Sylvie Mader 1*

1 Universite de Montreal 2 University of Illinois College of Medicine

* Address correspondence to: E-mail: sylvie.mader{at}umontreal.ca

Abstract

The bulky side chains of antiestrogens hinder folding of the ligand-binding domain (LBD) of estrogen receptors (ERs) into a transcriptionally active conformation. The presence of a tertiary amine in the side chain of raloxifene, which interacts with a negatively charged residue in helix H3 of the ER LBD (D351 in hER{alpha}), is important for antiestrogenicity in animal and cellular models. Here we have examined the influence of tertiary amine substituents and of mutations at position 351 in hER{alpha} on the activity profiles of tamoxifen derivatives. Results obtained in several cellular model systems suggest that the degree of antagonist activity of tamoxifen derivatives does not strictly correlate with the basicity of the side chain, but depends on an optimal spatial relationship between the tertiary amine of these antiestrogens and the negative charge at position 351. While displacement of the negative charge at position 351 (mutation D351E) had little effect on transcriptional activity in the presence of tamoxifen, it drastically increased the partial agonist activity of a tamoxifen derivative with improved antagonist activity as well as that of raloxifene. Our results suggest that contrary to raloxifene, tamoxifen and most of its derivatives do not interact with D351 in an optimal manner, although this can be improved by modifying tertiary amine substituents


Key words: Sex hormones, Structure-activity relationships and modeling, Transcription targets


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