@article{a0127d280dd24c6abd6f3c3bacb89e55,
title = "10β,17α-Dihydroxyestra-1,4-dien-3-one: A Bioprecursor Prodrug Preferentially Producing 17α-Estradiol in the Brain for Targeted Neurotherapy",
abstract = "Uterotrophic effect of 17α-estradiol, the C17 epimer of the main human estrogen 17β-estradiol, was shown to manifest in animal models at doses lower than those necessary for central outcome raising concerns about its potential to treat maladies of the central nervous system. We introduce here 10β,17α-dihydroxyestra-1,4-dien-3-one (α-DHED) that acts as a bioprecursor prodrug producing 17α-estradiol with remarkable selectivity to the brain and, therefore, without appreciable exposure of the periphery to the parent steroid. This distinguishing feature of α-DHED is shown by using an estrogen-responsive mouse model with complementary LC-MS/MS measurement of drug contents in target tissues. Our data warrant further research to fully establish the potential of α-DHED for a safe and efficacious 17α-estradiol-based neurotherapy.",
keywords = "10β,17α-dihydroxyestra-1,4-dien-3-one, 17α-Estradiol, ERs binding, LC-MS/MS, Porsolt swim test, brain-selective bioprecursor prodrug, ovariectomized mice, uterotrophic effect, α-DHED",
author = "Katalin Prokai-Tatrai and Vien Nguyen and Laszlo Prokai",
note = "Funding Information: The project was supported in part by the National Institutes of Health, in particular Grant Numbers EY027005 to K.P.-T. and CA215550 to L.P., and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.). Funding Information: *Email: Katalin.Prokai@unthsc.edu. Phone: 817-735-0617. ORCID Katalin Prokai-Tatrai: 0000-0001-5595-1346 Author Contributions K.P.-T. and L.P. contributed equally. K.P.-T. designed research, synthesized α-DHED, analyzed data, and wrote the manuscript. V.N. conducted animal studies and ran bioanalytical assays. L.P. designed research, conducted computational studies, analyzed data, and cowrote the manuscript. All authors have given approval to the final version of the manuscript. Funding The project was supported in part by the National Institutes of Health, in particular Grant Numbers EY027005 to K.P.-T. and CA215550 to L.P., and by the Robert A. Welch Foundation (endowment BK-0031 to L.P.). Notes The authors declare the following competing financial interest(s): K.P.-T. and L.P. are inventors in the patents covering the use of steroidal quinols as CNS-agents and are cofounders of AgyPharma LLC with equity in the company that licensed the patents. Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",
year = "2018",
month = nov,
day = "21",
doi = "10.1021/acschemneuro.8b00184",
language = "English",
volume = "9",
pages = "2528--2533",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "11",
}