TY - JOUR
T1 - Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator - A hybrid structure of 17β-estradiol and vitamin E in hippocampal neurons
AU - Zhao, Liqin
AU - Jin, Chunyang
AU - Mao, Zisu
AU - Gopinathan, Madathil B.
AU - Rehder, Kenneth
AU - Brinton, Roberta D.
PY - 2007/9/6
Y1 - 2007/9/6
N2 - 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.
AB - 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.
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U2 - 10.1021/jm070546x
DO - 10.1021/jm070546x
M3 - Article
C2 - 17696335
AN - SCOPUS:34548507935
SN - 0022-2623
VL - 50
SP - 4471
EP - 4481
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -