Design, Synthesis, and Estrogenic Activity of a Novel Estrogen Receptor Modulator--a Hybrid Structure of 17beta-estradiol and Vitamin E in Hippocampal Neurons.
From: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.
Journal of medicinal chemistry
- Publish Date: Sep 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 18
- Pages: 4471-81
- Medium: Print
- Language: English
- Citation (JAMA): Zhao Liqin, Jin Chunyang, Mao Zisu, et al. 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. Sep 2007;50:4471-81
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.
Mesh Headings (Keywords): Animals, Binding, Competitive, Cell Survival, Cells, Cultured, Computer Simulation, Drug Design, Estradiol, Estrogen Receptor Modulators, Estrogen Receptor alpha, Estrogen Receptor beta, Estrogens, Hippocampus, Humans, Models, Molecular, Neurons, Neuroprotective Agents, Rats, Stereoisomerism, Vitamin E
Check for Full Text / PubMed Unique Identifier (PMID): 17696335
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