Action of "pure" antiestrogens in inhibiting estrogen receptor action.

The mechanism of action of the pure antiestrogens ICI 164384 and ICI 182780 has been investigated. Both antagonists are steroidal antiestrogens with 7 alpha-alkylamide side-chains. The antiestrogens reduce the cellular content of the estrogen receptor by reducing the half-life of the protein. A potential mechanism for this effect is suggested by the observation that the DNA binding activity of receptors which have been over-expressed in cells was inhibited in vitro. The inhibitory activity of analogues of ICI 164384 with different side chain lengths correlates with their ability to function as pure antiestrogens in vivo. Since the estrogen binding site overlaps with residues involved in dimerisation, the antiestrogens are likely to bind to a similar site and may therefore with receptor dimerisation in the hormone binding domain by means of the 7 alpha side-chain. We propose that the increased turnover of the receptor in the presence of ICI 164384 and ICI 182380 is a consequence of impaired dimerisation of the proteins.