Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons.
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.
Zhao
Liqin
L
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.
Jin
Chunyang
C
Mao
Zisu
Z
Gopinathan
Madathil B
MB
Rehder
Kenneth
K
Brinton
Roberta D
RD
D000818:Animals; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D015195:Drug Design; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism; D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077267:Fulvestrant; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C523910:7-(4,8,12-trimethyltridecyl)estra-1,3,5-trien-3,17-diol; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018696:Neuroprotective Agents; D014810:Vitamin E; D000077267:Fulvestrant; D004958:Estradiol