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

Liqin Zhao, Chunyang Jin, Zisu Mao, Madathil B. Gopinathan, Kenneth Rehder, Roberta D. Brinton

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)4471-4481
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number18
DOIs
StatePublished - Sep 6 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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