page_title: Selective estrogen receptor modulator
section_title: Second-generation benzothiophenes
hierarchical_section_title: Selective estrogen receptor modulator / Structure and function / Structure–activity relationships / Second-generation benzothiophenes
caption_attribution_description: English: Raloxifene has a benzothiophene group (red) and a phenyl 4-piperidinoethoxy side chain (green).
context_page_description: Selective estrogen receptor modulators are a class of drugs that act on the estrogen receptor. A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
context_section_description: Raloxifene ([6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(1-piperidyl)ethoxy]phenyl]-methanone; see figure 9) belongs to the second-generation benzothiophene SERM drugs. It has a high affinity for the ER with potent antiestrogenic activity and tissue-specific effects distinct from estradiol. Raloxifene is an ER agonist in bone and the cardiovascular system, but in breast tissue and the endometrium it acts as an ER antagonist. It is extensively metabolized by glucuronide conjugation in the gut and because of that has a low bioavailability of only 2% while that of tamoxifen and toremifene is approximately 100%.
  The advantage of raloxifene over the triphenylethylene tamoxifen is reduced effect on the uterus. The flexible hinge group, as well as the antiestrogenic phenyl 4-piperidinoethoxy side chain, are important for minimizing uterine effects. Because of its flexibility the side chain can obtain an orthogonal disposition relative to the core so that the amine of raloxifens side chain is 1 Å closer than tamoxifens to amino acid Asp-351 in ERα's ligand-binding domain.
  The critical role of the intimate relationship between the hydrophobic side chain of raloxifene and the hydrophobic residue of the receptor to change both the shape and charge of the external surface of a SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 is increased from 2.7 Å to 3.5-5 Å it causes increased estrogen-like action of the raloxifene-ERα complex. When the piperidine ring of raloxifene is replaced by cyclohexane, the ligand loses antiestrogenic properties and becomes a full agonist. The interaction between SERM's antiestrogenic side chain and amino acid Asp-351 is the important first step in silencing AF-2. It relocates helix 12 away from the ligand-binding pocket thereby preventing coactivators from binding to the SERM-ER complex.
caption: Figure 9: Raloxifene has a benzothiophene group (red) and is connected with a flexible carbonyl hinge to a phenyl 4-piperidinoethoxy side chain (green).
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