Synthesis and Evaluation of (17α,20Z)-21-(4-Substituted-phenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17β-diols as Ligands for the Estrogen Receptor-α Hormone Binding Domain:  Comparison with 20E-Isomers

As part of our ongoing program to develop probes for the hormone binding domain of the estrogen receptor-α (ERα), we prepared and evaluated a series of 17α,Z-(4-substituted-phenyl)vinyl estradiol derivatives. The results indicated that the relative binding affinities (RBAs) at 25 °C for the new compounds were significant (RBA = 9−57) although less than that of estradiol (RBA = 100) or of the parent unsubstituted phenylvinyl estradiol (RBA = 66). All of the Z-compounds were full agonists in the uterotrophic assay, indicating that the ligands formed estrogen-like complexes with the estrogen receptor-α hormone binding domain (ERα-HBD). Comparison of corresponding Z- and E-4-substituted phenylvinyl ligands complexed with the ERα-HBD indicated small but significant differences in binding modes that may account for the differing trends seen in the structure−activity relationships for the two series.