New antiprogestins with partial agonist activity: Potential selective progesterone receptor modulators (SPRMs) and probes for receptor- and coregulator-induced changes in progesterone receptor induction properties

A pharmacologically relevant property of steroid hormone-regulated gene ind uction is the partial agonist activity of antisteroid complexes. We now rep ort that dexamethasone-mesylate (Dex-Mes) and dexamethasone-oxetanone (Dex- Ox), each a derivative of the glucocorticoid-selective steroid dexamethason e (Dex), are two new antiprogestins with significant amounts of agonist act ivity with both the A and B isoforms of progesterone receptor (PR), for dif ferent progesterone-responsive elements, and in several cell lines. These c ompounds continue to display activity under conditions where another partia l antiprogestin (RTI-020) is inactive. These new antiprogestins were used t o determine whether the partial agonist activity of PR complexes can be mod ified by changing concentrations of receptor or coregulator, as we have rec ently demonstrated for glucocorticoid receptors (GRs). Because GR and coreg ulator concentrations simultaneously altered the position of the physiologi cally relevant dose-response curve, and associated EC50 of GR-agonist compl exes, we also examined this phenomenon with PR. We find that elevated PR or transcriptional intermediary factor 2 (TIF2) concentrations increase the p artial agonist activity of Dex-Mes and Dex-Ox, and the EC50 of agonists, in dependently of changes in total gene transactivation. Furthermore, the core pressors SMRT (silencing mediator for retinoid and thyroid receptors) and N CoR (nuclear receptor corepressor) each suppresses gene induction but NCoR acts opposite to SMRT and, like the coactivator TIF2, reduces the EC50 and increases the partial agonist activity of antiprogestins. These comparable responses of GR and PR suggest that variations in receptor and coregulator concentrations may be a general mechanism for altering the induction proper ties of other steroid receptors. Finally, the magnitude of coregulator effe cts on PR induction properties are often not identical for agonists and the new antagonists, suggesting subtle mechanistic differences. These properti es of Dex-Mes and Dex-Ox, plus the sensitivity of their activity to cellula r differences in PR and coregulator concentrations, make these steroids pot ential new SPRMs (selective progesterone receptor modulators) that should p rove useful as probes of PR induction properties.