DISSECTION OF THE MOLECULAR MECHANISM OF ACTION OF GW5638, A NOVEL ESTROGEN-RECEPTOR LIGAND, PROVIDES INSIGHTS INTO THE ROLE OF ESTROGEN-RECEPTOR IN BONE

The estrogen receptor (ER) mixed agonists tamoxifen and raloxifene hav e been shown to protect against bone loss in ovariectomized rats. Howe ver, the mechanism by which these compounds manifest their activity in bone is unknown. We have used a series of in vitro screens to select for compounds that are mechanistically distinct from tamoxifen and ral oxifene in an effort to define the properties of an ER modulator requi red for bone protection. Using this approach, we identified a novel hi gh affinity ER antagonist, GW5638, which when assayed in vitro functio ns as an ER antagonist, inhibiting the agonist activity of estrogen, t amoxifen, and raloxifene and reversing the ''inverse agonist'' activit y of the pure antiestrogen ICI182,780. Thus, GW5638 appears to functio n as an antagonist in these in vitro systems, although in a manner dis tinct from other known ER modulators. Predictably, therefore, GW5638 a lone displays minimal uterotropic activity in ovariectomized rats, but will inhibit the agonist activity of estradiol in this environment. U nexpectedly, however, this compound functions as a full ER agonist in bone and the cardiovascular system. These data suggest that the mechan ism by which ER operates in different cells is not identical, and that classical agonist activity is not required for the bone protective ac tivity of ER modulators.