10β,17α-Dihydroxyestra-1,4-dien-3-one: A Bioprecursor Prodrug Preferentially Producing 17α-Estradiol in the Brain for Targeted Neurotherapy

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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.

Original languageEnglish
Pages (from-to)2528-2533
Number of pages6
JournalACS Chemical Neuroscience
Volume9
Issue number11
DOIs
Publication statusPublished - 21 Nov 2018

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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

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