Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. Academic Article uri icon

start page

  • 358

end page

  • 366

abstract

  • GPER/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone substituent in G15 could minimize key steric conflicts, present in G-1, that limit binding within the ER? ligand binding pocket. In this report, we identify low-affinity cross-reactivity of the GPER antagonist G15 to the classical estrogen receptor ER?. To generate an antagonist with enhanced selectivity, we therefore synthesized an isosteric G-1 derivative, G36, containing an isopropyl moiety in place of the ethanone moiety. We demonstrate that G36 shows decreased binding and activation of ER?, while maintaining its antagonist profile towards GPER. G36 selectively inhibits estrogen-mediated activation of PI3K by GPER but not ER?. It also inhibits estrogen- and G-1-mediated calcium mobilization as well as ERK1/2 activation, with no effect on EGF-mediated ERK1/2 activation. Similar to G15, G36 inhibits estrogen- and G-1-stimulated proliferation of uterine epithelial cells in vivo. The identification of G36 as a GPER antagonist with improved ER counterselectivity represents a significant step towards the development of new highly selective therapeutics for cancer and other diseases.Copyright © 2011 Elsevier Ltd. All rights reserved.

date/time value

  • 2011

Digital Object Identifier (DOI)

  • 10.1016/j.jsbmb.2011.07.002

PubMed Identifier

  • 21782022

volume

  • 127

number

  • 3-5

keywords

  • Animals
  • Binding Sites
  • Blotting, Western
  • COS Cells
  • Cercopithecus aethiops
  • Magnetic Resonance Spectroscopy
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Spectrometry, Mass, Electrospray Ionization
  • Spectroscopy, Fourier Transform Infrared