title: New-D-homoandrost-4,6-diene derivatives as potent progesterone receptor antagonist.
abstract: 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.
authors.affiliation: Department of Biological Systems and Animal Production Metropolitan University-Xochimilco, Mexico D. F., Mexico. marisa@correo.xoc.uam.mx
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
authors.forename: Mario
authors.initials: M
authors.lastname: García-Lorenzana
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcés
authors.forename: Ivonne
authors.initials: I
authors.lastname: Heuze
authors.forename: Nayeli
authors.initials: N
authors.lastname: Teran
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
mesh_terms: D059002:Androgen Receptor Antagonists; D000730:Androstadienes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000735:Androstenedione / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D003338:Corpus Luteum / Q000187:drug effects / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006718:Homosteroids / Q000737:chemistry / Q000494:pharmacology; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: C549236:17-methyl-16-phenyl-17-(2-fluorophenyl)acetoxyhomoandrost-4,6-diene-3,17a-dione; C549237:17-methyl-16-phenyl-17-(3-fluorophenyl)acetoxyhomoandrost-4,6-diene-3,17a-dione; C549235:17-methyl-16-phenyl-17-phenylacetoxyhomoandrost-4,6-diene-3,17a-dione; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D006718:Homosteroids; D006727:Hormone Antagonists; D010648:Phenylacetates; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D015735:Mifepristone; D007987:Gonadotropin-Releasing Hormone; D000735:Androstenedione; D011374:Progesterone