Just like in 4-hydroxytamoxifen, the bulky side chain of raloxifene displaces helix 12. Third-generation Lasofoxifene interaction with ERα is typical of those between SERM-ERα such as a nearly planar topology (the tetrahydronapthalene carbocycle), hydrogen bonding with Arg-394 and Glu-353 and the phenyl side chains of lasofoxifene filling the C-ring and D-ring volume of the ligand-binding pocket. Lasofoxifene diverts helix 12 and prevents the binding of coactivator proteins with LXXLL motives. This is achieved by lasofoxifene occupying the space normally filled by Leu-540's side group and modulating the conformation of residues of helix 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with helix 12 positioning by the drug's ethyl pyrrolidine group. In vitro studies indicate that bazedoxifene competitively blocks 17β-estradiol by high and similar binding to both ERα and ERβ. Bazedoxifenes main binding domain consists of the 2-phenyl-3-methylindole and a hexamethylenamine ring at the side chain affected region. Ospemifene is an oxidative deaminated metabolite of toremifene as has a similar binding to ER as toremifene and tamoxifen. The competitive binding to ERα and ERβ of the three metabolites 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and the 4-hydroxy-, side chain carboxylic acid Ospemifene is at least as high as the parent compound. History The discovery of SERMs resulted from attempts to develop new contraceptives. Clomifene and tamoxifen prevented conception in rats but did the opposite in humans. Clomifene successfully induced ovulation in subfertile women and on February 1, 1967, it was approved in the US for the treatment of ovulatory dysfunction in women who were trying to conceive. Toxicological issues prevented long term use of clomifene and further drug development for other potential applications such as breast cancer treatment and prevention. It was another ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer. The discovery in 1987 that the SERMs tamoxifen and raloxifene, then thought to be antiestrogens because of antagonist effects in breast tissue, showed estrogenic effects in preventing bone loss in ovariectomized rats had a great effect on our understanding of the function of estrogen receptors and nuclear receptors in general. The term SERM was introduced to describe these compounds that have a combination of estrogen agonist, partial agonist, or antagonist activities depending on the tissue. Toremifene has been shown to be compatible with tamoxifen, and in 1996 it was approved for use in the treatment of