In vivo estrogen bioactivities and in vitro estrogen receptor binding and transcriptional activities of anticoagulant synthetic 17 beta-aminoestrogens

Estrogenic activities of the two 17 beta-aminoestrogen (AE) derivatives, pr olame and butolame, were studied upon coagulation, serum luteinizing hormon e (LH) and uterine weight, including endometrial morphology in castrated fe male rats. We have also investigated the ability of these two compounds, as well as another AE pentolame, to activate transcription through the estrog en receptor alpha (ER alpha) and the estrogen receptor beta (ER beta). Admi nistration of prolame and butolame to castrated animals increased significa ntly (P < 0.01) the mean clotting time when compared with that obtained in the group of control animals. Butolame was a more potent anticoagulant than prolame (P < 0.01); as judged by their corresponding IC50 (5.4 +/- 0.65 an d 66.6 +/- 2.57 mu g/animal, respectively). In contrast, estradiol signific antly shortened blood clotting times (P < 0.005). Both prolame and butolame caused a significant inhibition of serum LH levels (EC50 8.10 +/- 0.79 and 17 +/- 64 mu g/animal, respectively), and restored castration-induced redu ction in uterine weight of ovariectomized rats (EC50 4.14 +/- 1.57 and 17.0 +/- 1.78 mu g/animal, respectively). In terms of the effects of prolame, b utolame and pentolame in transient transfection assays, all the three AE ac tivated ER dependent reporter gene expression, however, only at high concen trations. Prolame had the highest activity followed by butolame and pentola me. Induction of transcription by these compounds was preferentially mediat ed through the ER alpha, especially in the case of pentolame where little, if any, activation occurred through the ER beta. None of the compounds show ed antagonistic activities through either ER subtype. The overall data sugg est that modifications in the structure and length of the amino-alcohol sid e-chain at C-17 might have an impact on the affinity and estrogenic intrins ic properties of AE at the level of diverse target tissues. (C) 2000 Elsevi er Science Ltd. All rights reserved.