Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.

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Zhao L, Jin C, Mao Z, Gopinathan MB, Rehder K, Brinton RD

Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.

J Med Chem. 2007 Sep 6;50(18):4471-81. Epub 2007 Aug 14.

PubMed ID
17696335 [ View in PubMed
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Abstract

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

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
EstradiolEstrogen receptor alphaIC 50 (nM)4.7N/AN/ADetails
EstradiolEstrogen receptor betaIC 50 (nM)16.7N/AN/ADetails
FulvestrantEstrogen receptor alphaIC 50 (nM)4.9N/AN/ADetails
GenisteinEstrogen receptor alphaIC 50 (nM)2150N/AN/ADetails
GenisteinEstrogen receptor betaIC 50 (nM)45900N/AN/ADetails