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Vol. 54, Issue 1, 105-112, July 1998
and Estrogen
Receptor 
to Partial Estrogen Agonists/Antagonists
Karo Bio AB (T.B., B.C., Y.N., S.N.),
Center for Biotechnology
(E.E.), and
Department of Medical Nutrition (J.-Å.G.), Novum, S-141 57 Huddinge, Sweden
The existence of two rather than one estrogen receptor, today
characterized as estrogen receptor 
(ER) and estrogen receptor 
(ER), indicates that the mechanism of action of 17-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 is high compared with those amino acid residues in ER LBD, 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-ethynyl,17-estradiol, for example, has an ER-selective
agonist potency and that 16,17-epiestriol has an ER-selective
agonist potency. We also report that genistein has an ER-selective
affinity and potency but an ER-selective efficacy. Furthermore, we
show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have
an ER-selective partial agonist/antagonist function but a pure
antagonist effect through ER. In addition, raloxifene displayed an
ER-selective antagonist potency, in agreement with its
ER-selective affinity. However, although ICI 164,384 showed an
ER-selective affinity, it had a similar potency to antagonize the
effect of 17-estradiol in the ER- and ER-specific reporter
cell lines, respectively. In conclusion, our data indicate that the
ligand binding cavity of ER is probably more different from that of
ER 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.
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