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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding, Competitive
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Cell Survival / drug effects
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Cells, Cultured
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Computer Simulation
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Drug Design
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Estradiol / analogs & derivatives*
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Estradiol / chemical synthesis*
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Estradiol / chemistry
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Estradiol / pharmacology
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Estrogen Receptor Modulators / chemical synthesis*
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Estrogen Receptor Modulators / chemistry
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Estrogen Receptor Modulators / pharmacology
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor beta / agonists
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Estrogen Receptor beta / metabolism
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Estrogens / chemical synthesis*
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Estrogens / chemistry
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Estrogens / pharmacology
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Fulvestrant
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Hippocampus / cytology
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Humans
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Models, Molecular
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Neurons / cytology
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Neurons / drug effects*
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology
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Rats
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Stereoisomerism
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Vitamin E / analogs & derivatives*
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Vitamin E / chemical synthesis*
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Vitamin E / chemistry
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Vitamin E / pharmacology
Substances
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7-(4,8,12-trimethyltridecyl)estra-1,3,5-trien-3,17-diol
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Estrogen Receptor Modulators
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Estrogens
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Neuroprotective Agents
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Vitamin E
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Fulvestrant
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Estradiol