title: Novel 17 substituted pregnadiene derivatives as 5 alpha-reductase inhibitors and their binding affinity for the androgen receptor.
abstract: The in vitro antiandrogenic activity of four new progesterone derivatives: 4, 5, 6 and 7 (8 is a known compound) was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as by their capacity to bind to the androgen receptor in gonadectomized hamster prostate. The IC(50) value was determined using increasing concentrations of 4, 5, 6, 7 and 8 in the presence of [(3)H]T and the microsomal fraction of the hamster prostate containing the 5alpha-reductase enzyme. In this paper we also demonstrated the effect of increasing concentrations of the novel steroids upon [(3)H]DHT binding to the androgen receptors from hamster prostate which produces competition for the androgen receptor sites. The in vitro studies showed that steroids 4, 5, 6, 7 and 8 had an inhibitory activity for the 5alpha-reductase with IC(50) of: 4 (0.17 microM), 5 (0.19 microM), 6 (1 microM), 7 (4.2 microM), and 8 (2.7 microM). On the other hand, the IC(50) value for compounds 4, 5, 6, 7, 8 and DHT showed the following order of affinity for the androgen receptor: 6>7>5>DHT. Surprisingly compounds 4 and 8 did not bind to the androgen receptor. The overall data indicate that all synthesized compounds are inhibitors for the enzyme 5alpha-reductase present in the hamster prostate. In contrast, compounds 5, 6 and 7, which have a cyclohexyl group in the side chain showed a high affinity for the androgen receptor.
authors.affiliation: Department of Biological Systems and Animal Production, Metropolitan University-Xochimilco, Mexico, DF Mexico. marisa@cueyatl.uam.mx
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
authors.forename: Eugenio
authors.initials: E
authors.lastname: Flores
authors.forename: Ivonne
authors.initials: I
authors.lastname: Heuze
authors.forename: Mauricio
authors.initials: M
authors.lastname: Sánchez
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.forename: Elena
authors.initials: E
authors.lastname: Ramírez
authors.forename: Victor Alfonso
authors.initials: VA
authors.lastname: Francolugo
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D011245:Pregnadienes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D004791:Enzyme Inhibitors; D011245:Pregnadienes; D011944:Receptors, Androgen; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase