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

New compounds have been synthesized based on the structure of the anti-tumo ral drug tamoxifen and its diphenylmethane derivative, N,N-diethyl-2-[(4-ph enyl-methyl)-phenoxy]-ethanamine HCl (DPPE). These new compounds have no af finity 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 a nd 23b have 1.2 and 3.5 higher affinity than tamoxifen. Three-dimensional s tructure analysis, performed using the intersection of the van der Waals vo lume occupied by tamoxifen in its crystallographic state and the van der Wa als volume of these new compounds in their calculated minimal energy confor mation, 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 highl y specific for AEBS. Since these compounds do not bind ER they will be help ful to study AEBS mediated cytotoxicity. Moreover our study shows that our strategy is a new useful guide to design high affinity and selective ligand s for AEBS. (C) 2000 Elsevier Science Ltd. All rights reserved.