Differential response of estrogen receptor subtypes to 1,3-diarylindene and 2,3-diarylindene ligands

Nicola J. Clegg, Sreenivasan Paruthiyil, Dale C. Leitman, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERα and ERβ in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERα and ERβ subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERα, while antagonizing estradiol action at ERβ.

Original languageEnglish (US)
Pages (from-to)5989-6003
Number of pages15
JournalJournal of Medicinal Chemistry
Volume48
Issue number19
DOIs
StatePublished - Sep 22 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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