Differential response of estrogen receptor α and estrogen receptor β to partial estrogen agonists/antagonists

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta), indicates that the mechanism of action of 17 beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ER beta is high compared with those amino acid residues in ER alpha LED, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17 alpha-ethynyl,17 beta-estradiol, for example, has an ER alpha-selective agonist potency and that 16 beta,17 alpha-epiestriol has an ERP-selective agonist potency. We also report that genistein has an ER beta-selective affinity and potency but an ER alpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ER alpha-selective partial agonist/ antagonist function but a pure antagonist effect through ER beta. In addition, raloxifene displayed an ER alpha-selective antagonist potency, in agreement with its ER alpha-selective affinity. However, although ICI 164,384 showed an ER beta-selective affinity, it had a similar potency to antagonize the effect of 17 beta-estradiol in the ER alpha- and ER beta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ER beta is probably more different from that of ER alpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs.