Synthesis, binding and structure-affinity studies of new ligands for the microsomal anti-estrogen binding site (AEBS)

Bioorg Med Chem. 2000 Aug;8(8):2007-16. doi: 10.1016/s0968-0896(00)00119-x.


New compounds have been synthesized based on the structure of the anti-tumoral drug tamoxifen and its diphenylmethane derivative, N,N-diethyl-2-[(4-phenyl-methyl)-phenoxy]-ethanamine, HCl (DPPE). These new compounds have no affinity for the estrogen receptor (ER) and bind with various affinity to the anti-estrogen binding site (AEBS). Compounds 2, 10, 12, 13, 20a, 20b, 23a, 23b, 29 exhibited 1.1-69.5 higher affinity than DPPE, and compounds 23a and 23b have 1.2 and 3.5 higher affinity than tamoxifen. Three-dimensional structure analysis, performed using the intersection of the van der Waals volume occupied by tamoxifen in its crystallographic state and the van der Waals volume of these new compounds in their calculated minimal energy conformation, correlated well with their pKi for AEBS (r = 0.84, P<0.0001, n = 18). This is the first structure-affinity relationship (SAR) ever reported for AEBS ligands. Moreover in this study we have reported the synthesis of new compounds of higher affinity than the lead compounds and that are highly specific for AEBS. Since these compounds do not bind ER they will be helpful to study AEBS mediated cytotoxicity. Moreover our study shows that our strategy is a new useful guide to design high affinity and selective ligands for AEBS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Microsomes / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Phenyl Ethers / chemistry*
  • Phenyl Ethers / metabolism
  • Radioligand Assay
  • Rats
  • Receptors, Drug / chemistry
  • Receptors, Drug / metabolism*
  • Selective Estrogen Receptor Modulators / chemical synthesis*
  • Selective Estrogen Receptor Modulators / chemistry*
  • Selective Estrogen Receptor Modulators / metabolism
  • Structure-Activity Relationship
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / chemistry
  • Tamoxifen / metabolism


  • Ligands
  • Phenyl Ethers
  • Receptors, Drug
  • Selective Estrogen Receptor Modulators
  • Tamoxifen
  • tesmilifene