Abstract
The steroid hormones estrogen and progesterone together regulate the development and maintenance of the female reproductive system. The actions of these two hormones are mediated by their respective nuclear receptors located within overlapping cell populations in target organs. The molecular mechanism of action of these two hormones has been defined to a large extent using estrogen receptor (ER) and progesterone receptor (PR) antagonists. In the case of ER, the available antagonists are highly receptor selective. With respect to PR, however, the available antiprogestins also interact with the receptors for glucocorticoids, mineralocorticoids, and androgens. Whereas these cross-reactivities can usually be managed in studies of female reproductive function, it is the recent demonstration that RU486 is an effective antagonist of the β-isoform of ER that suggested the need for more selective antiprogestins. In this study, we used cell-based transcriptional assays combined with screens using coactivator peptide analogs to identify two novel classes of antiprogestins that distinguish themselves from the antiprogestin RU486 in the manner they interact with PR. One class exhibits the characteristics of a pure antiprogestin in that its members bind to the receptor and induce a conformational change that prevents the presentation of two potential coactivator binding surfaces on the protein. The second class of compounds distinguish themselves from RU486 in that they are ERβ sparing. When tested in vivo the ER-sparing antiprogestins were as effective as RU486 in suppressing superovulation. It is anticipated that the availability of these new antiprogestins will advance the studies of PR pharmacology in a manner similar to how the availability of selective ER modulators has helped the study of ER action.
Identification and Characterization of Murine Cytotoxic T Cells That Kill Mycobacterium tuberculosis
