A novel prodrug approach for central nervous system-selective estrogen therapy

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Beneficial effects of estrogens in the central nervous system (CNS) results fromthe synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.

Original languageEnglish
Article number4197
JournalMolecules
Volume24
Issue number22
DOIs
StatePublished - 19 Nov 2019

Keywords

  • Antioxidant
  • Bioprecursor prodrug
  • Brain
  • CNS-selective estrogen therapy
  • Cognition
  • Cognition
  • DHED
  • Depression
  • Estrogens
  • Glaucoma
  • Menopause
  • Neuroprotection
  • Para-quinol
  • Photoreceptor
  • Retina
  • Stroke

Fingerprint Dive into the research topics of 'A novel prodrug approach for central nervous system-selective estrogen therapy'. Together they form a unique fingerprint.

  • Cite this