New- D-homoandrost-4,6-diene derivatives as potent progesterone receptor antagonist

• Published in: Steroids 2010, Vol.75 (1), p.101-108
• Main Authors: Cabeza, Marisa, García-Lorenzana, Mario, Garcés, Montserrat, Heuze, Ivonne, Teran, Nayeli, Bratoeff, Eugene
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists; Androgen receptors; Androstadienes - chemistry; Androstadienes - metabolism; Androstadienes - pharmacology; Androstenedione - analogs & derivatives; Androstenedione - chemistry; Androstenedione - pharmacology; Animals; Antagonist of the progesterone receptors; Binding, Competitive; Biological and medical sciences; Corpus Luteum - drug effects; Corpus Luteum - metabolism; Endometriosis; Endometrium - drug effects; Endometrium - metabolism; Female; Female genital diseases; Gonadotropin-Releasing Hormone - pharmacology; Gynecology. Andrology. Obstetrics; Homosteroids - chemistry; Homosteroids - pharmacology; Hormone Antagonists - chemistry; Hormone Antagonists - metabolism; Hormone Antagonists - pharmacology; Male; Medical sciences; Mice; Mifepristone - chemistry; Mifepristone - metabolism; Mifepristone - pharmacology; Molecular Structure; New D-homoandrost-4,6-diene derivatives; Non tumoral diseases; Ovary - drug effects; Ovary - metabolism; Phenylacetates - chemistry; Progesterone - chemistry; Progesterone - metabolism; Progesterone - pharmacology; Rabbits; Rats; Receptors, Androgen - metabolism; Receptors, Progesterone - antagonists & inhibitors; Receptors, Progesterone - metabolism; Structure-Activity Relationship; Uterine histology; Uterus - drug effects; Uterus - metabolism
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2009.11.001

The aim of this study was to synthesize three different D-homoandrostadiene derivatives ( 2– 4) and study their biological activity. We carried out in vivo and in vitro experiments using female cycling mice, which were synchronized for estrus with luteinizing hormone-releasing hormone (LHRH) and injected with the steroidal compounds. It was also determined the binding of these compounds to the progesterone receptors (PR). Since these steroids have a new D-homoandrostandienone skeleton in their molecular structure, it was of interest also to study their binding to the androgen receptors (AR). After LHRH treatment, the mice of the control group showed the presence of 14 ± 4 corpus lutea in the ovary whereas the animals treated with steroids 2– 4, with RBAs of 100%, exhibited 11 ± 7, 12 ± 2, and 10 ± 4 respectively. As a result of this study, it is evident that these steroids did not inhibit the ovulation in these animals. The uterus of the control group, showed the typical progestational activity with an enlarged endometrial thickness with a secretory activity. However, the endometrium of the mice treated with steroids 2– 4 did not show an enlargement of the endometrium and no secretory activity could be detected. This fact indicates that compounds 2– 4 had antagonistic activity in this tissue. The overall data show that steroids 2– 4 are antagonists of the PR. However, they do not bind to the AR. These results also demonstrate that 2– 4 have an antiprogestational activity in vivo, but do not decrease the number of corpus lutea in the ovary of mice treated with LHRH.