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Design, Synthesis, and Estrogenic Activity of a Novel Estrogen Receptor ModulatorA Hybrid Structure of 17β-Estradiol and Vitamin E in Hippocampal Neurons

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journal contribution
posted on 06.09.2007, 00:00 by Liqin Zhao, Chunyang Jin, Zisu Mao, Madathil B. Gopinathan, Kenneth Rehder, Roberta D. Brinton
We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7α-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17β-diol (2), a hybrid structure of 17β-estradiol and vitamin E, was synthesized and found to bind to both ERα and ERβ. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.