Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens.

Abstract The binding of estradiol (E 2 ) to estrogen receptors (ER) is followed by conformational changes resulting in coactivator or corepressor recruitment that influences gene transcription. A series of synthetic A-ring reduced 19-nortestosterone-derived progestins has the capacity to selectively bind and activate transcription through the ERα. Herein, the molecular mechanisms involved in ER subtype-selective interactions of these compounds as assessed by their effects upon both ERα and ERβ structural conformation and their ability to induce recruitment of steroid receptor coactivator-1 (SRC-1) to ERα were investigated. The results demonstrated that all synthetic A-ring 3β,5α-tetrahydro-reduced derivatives of 19-nortestosterone induced an ERα trypsin digestion pattern similar to that seen with E 2 , without effects upon ERβ. In addition, these compounds had the ability to recruit SRC-1 to the ligand-binding domain of ERα similar to E 2 . Our data indicate that A-ring 3β,5α-tetrahydro-reduced 19-nortestosterone-derived progestins behave as selective ERα agonists with ligand–receptor structural and functional responses similar to those induced with natural E 2 .