Asunto(s)
Anestésicos/síntesis química , Homoesteroides/síntesis química , Pregnanos/síntesis química , Anestésicos/química , Anestésicos/metabolismo , Animales , Unión Competitiva , Encéfalo/metabolismo , Cristalografía por Rayos X , Electrofisiología , Homoesteroides/química , Homoesteroides/metabolismo , Técnicas In Vitro , Conformación Molecular , Oocitos , Pregnanos/química , Pregnanos/metabolismo , Ratas , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiología , Relación Estructura-Actividad , Xenopus laevisRESUMEN
Nine dioxygenated D-homoandrostanes were incubated with Rhizopus nigricans to investigate the effect of D-ring modification on microbiological hydroxylation. Structure determination of the products by NMR spectroscopy, and in certain cases independent synthesis of their oxidised products, showed that in contrast to 5 alpha-androstanes the majority of the compounds were hydroxylated in the "reverse" mode, and only D-homo-5 alpha-androstane-3,17-dione was hydroxylated in the "normal" mode to any extent. Stereospecific ring D-hydroxylation at C(17 alpha) was observed for both D-homo-5 alpha-androstane-3,6- and 3,7-diones.
Asunto(s)
Androstanos/metabolismo , Homoesteroides/metabolismo , Rhizopus/metabolismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Relación Estructura-ActividadRESUMEN
The equilibrium affinity constant for rat prostate androgen receptor and epididymal androgen binding protein (ABP) has been determined for thirty-four potential progestogens. Three A-nor-, four A,19-dinor-, and one A-homo-5 alpha-androstane derivative bind to the androgen receptor (KD less than 0.5 muM). Five of these compounds also bind to ABP with an affinity of the same order of magnitude. "Anordrin" (compound 24) and "Dinordrins" (compounds 10, 14, 15, 16, 17), which are potential female contraceptives, do not bind with high affinity to the androgen receptor or to ABP. The following modifications in A-nor derivatives favour binding to the receptor as compared to ABP: 19-nor substitution (compound 1), C-18 methyl homologation (compound 5), 2 alpha-ethinylation (compound 22). One 2 alpha-allenyl A-nor derivative (compound 25) and one A-homo derivative (compound 34) bind almost exclusively to ABP. The interaction with either binding protein is decreased by oxidation or esterification of the hydroxyl group at C-17, and by addition of a 17 alpha-ethinyl group. The latter modifications are likely to increase the specificity of androstane derivatives for receptors other than androgen binding proteins, such as the progesterone receptor.