Design, synthesis, and Estrogenic activity of a novel estrogen receptor modulator -: A hybrid structure of 17β-estradiol and vitamin E in hippocampal neurons

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. 7 alpha[(4R,8R)-4,8,-12-trimethyltridecyl]estra-1,3,5-trien-3,17 beta-diol (2), a hybrid structure of 17 beta-estradiol and vitamin E, was synthesized and found to bind to both ER alpha and ER beta. 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 I 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.