Novel Ligands that Function as Selective Estrogens or Antiestrogens for Estrogen Receptor- or Estrogen Receptor-

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Abstract
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, ERa and ERb. An aryl-substituted pyrazole is an ERa potency-selective agonist, showing higher binding affinity for ERa and 120-fold higher potency in stimulation of ERa vs. ERb in trans- activation assays in cells. A tetrahydrochrysene (THC) has a 4-fold preferential binding affinity for ERb; it is an agonist on ERa, but a complete antagonist on ERb. 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 ERa and ERb but has a 20-fold lower affinity for ERb than R,R-THC. This difference in bind- ing affinity accounts for the full ERb 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 ERb and ERa may play in the diverse target tissues in which estrogens act. (Endocrinology 140: 800 - 804, 1999) A S A MEDIATOR of the actions of estrogenic hormones, the estrogen receptor (ER) plays a central role in reg- ulating a diverse array of normal physiological processes involved in the development and function of the reproduc- tive system, as well as in many other aspects of health (car- diovascular, bone density, etc.), and estrogen pharmaceuti- cals have been developed to regulate these processes or their pathological counterparts, including infertility, breast can- cer, and osteoporosis. The recent discovery of a second es- trogen receptor, named estrogen receptor-b (ERb) to distin- guish it from the classical ER (now named ERa), has opened new possibilities by which estrogen pharmaceuticals might exert tissue- and cell-selective activity (1-3). These ER sub- types have significantly different primary sequences in their ligand binding and transactivation domains, with ERa and ERb showing 56% amino acid identity in their hormone binding domain/activation function-2 region and only ca. 20% homology in their A/B domain/activation function-1 region. This suggests that these ER subtypes might bind some ligands with different affinity and that these ligands might also have different agonist or antagonist character mediated by the two receptors. Because ERa and ERb have some overlapping but also some different tissue distributions (2- 4), differences in ligand interaction or activity with the two ERs could translate into important differences in their biological actions at the tissue level. To identify compounds that might have ER subtype-se- lective activity, we have examined some structurally diverse ER ligands and report on the identification of novel, non- steroidal ligands that show pronounced subtype-selective differences in binding affinity and in transcriptional potency or efficacy. Notably, one is an ERa potency-selective agonist, and another is an agonist on ERa but a complete antagonist on ERb. These compounds should be useful in structural studies on ER agonist and antagonist complexes, and in evaluating the distinct roles that ERb and ERa may play in the diverse target tissues in which estrogens act.

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