Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-α or estrogen receptor-β

We report on the identification of novel, nonsteroidal ligands that show pronounced subtype-selective differences in ligand binding and transcriptional potency or efficacy for the two estrogen receptor (ER) subtypes, ERα and ERβ. An aryl-substituted pyrazole is an ERα potency- selective agonist, showing higher binding affinity for ERα and 120-fold higher potency in stimulation of ERα vs. ERβ in transactivation assays in cells. A tetrahydrochrysene (THC) has a 4-fold preferential binding affinity for ERβ; it is an agonist on ERα, but a complete antagonist on ERβ. Intriguingly, the antagonist activity of THC is associated with the R,R- enantiomer (R,R-THC). The S,S-enantiomer (S,S-THC) is an agonist on both ERα and ERβ but has a 20-fold lower affinity for ERβ than R,R-THC. This difference in binding affinity accounts for the full ERβ antagonist activity of the THC racemate (a 1:1 mixture of R,R-THC and S,S-THC). These compounds should be useful in probing the conformational changes in these two ERs that are evoked by agonists and antagonists, and in evaluating the distinct roles that ERβ and ERα may play in the diverse target tissues in which estrogens act.