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Synthesis and Biological Evaluation of SERMs with Potent Nongenomic Estrogenic Activity
Author(s) -
Tobias Sandra C.,
Qiu Jian,
Kelly Martin J.,
Scanlan Thomas S.
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500098
Subject(s) - selective estrogen receptor modulator , estrogen receptor , estrogen , chemistry , transcription factor , receptor , pharmacology , nuclear receptor , signal transduction , raloxifene , medicine , endocrinology , biochemistry , biology , gene , cancer , breast cancer
We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ER α and ER β ). These compounds are analogues of 4‐hydroxytamoxifen, but unlike 4‐hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER‐mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST‐X , elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic γ‐aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST‐X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.