RESUMEN
The synthesis of a set of substituted 3-aryl-7-hydroxycoumarins was performed. The study of the relations between their structure and their relative binding affinity (RBA) to human alpha and B estrogen receptors was achieved.
Asunto(s)
Cumarinas/síntesis química , Receptores de Estrógenos/metabolismo , Células Cultivadas , Cumarinas/metabolismo , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Humanos , Indicadores y ReactivosRESUMEN
In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of substituted biphenyls. Their synthesis and binding affinity are described.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Estrógenos/efectos de los fármacos , Esteroides/química , Receptor alfa de Estrógeno , Humanos , Proteínas Recombinantes/efectos de los fármacosRESUMEN
The pharmacological profile of RU 58642, a new non-steroidal antiandrogen was investigated both in vitro and in vivo. In vitro, the compound displays a strong and specific affinity for androgen receptor. In vivo, its antiandrogenic activity was evaluated in castrated rat supplemented with testosterone propionate and in intact animals on prostate, seminal vesicles weight and serum levels of testosterone by oral and subcutaneous route. In castrated rats RU 58642 induced a significant decrease in prostate weight at a dose as low as 0.3 mg/kg whatever the route of administration. In intact rats its activity was compared to that of other non-steroidal antiandrogens such as flutamide, nilutamide and bicalutamide. RU 58642 proved to be significantly more potent than the reference compounds in reducing prostate weight: 3-30 times orally and 3-100 times subcutaneously, and thus the most potent antiandrogen to date to our knowledge. These results suggest that this compound may be very useful in the treatment of systemic androgen-dependent diseases.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Hidantoínas/farmacología , Imidazolidinas , Anilidas/farmacología , Animales , Flutamida/farmacología , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Genitales Masculinos/anatomía & histología , Genitales Masculinos/efectos de los fármacos , Genitales Masculinos/metabolismo , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Nitrilos , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/efectos de los fármacos , Testosterona/farmacología , Compuestos de TosiloAsunto(s)
Antagonistas de Hormonas/química , Antagonistas de Hormonas/farmacología , Antagonistas de Receptores Androgénicos , Animales , Femenino , Humanos , Masculino , Antagonistas de Receptores de Mineralocorticoides , Modelos Moleculares , Receptores Androgénicos/química , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/química , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/química , Relación Estructura-ActividadRESUMEN
New N-substituted arylthiohydantoin antiandrogens were synthesized. These compounds presented exceptionally high relative binding affinities (RBAs) for the rat androgen receptor (AR): up to 3 times that of testosterone (T) and 100 times the RBAs of non-steroidal antiandrogens such as flutamide, Casodex and Anandron. Furthermore, unlike available markers for AR, they were totally devoid of any binding to the other steroid receptors. RU 59063, the molecule with the highest RBA, was tritiated. When it was compared to [3H]T for the assay of rat, mouse, hamster and human AR, it gave rise to the same number of binding sites but its K alpha (6 x 10(9) M-1) for rat and human AR were, respectively 3 and 8 times higher than that of T. Moreover RU 59063, unlike T, was devoid of any specific binding to human plasma. In vivo, these compounds displayed antiandrogenic activity while being devoid of any agonistic effect. Thus, RU 56187, given orally in castrated male animals, prevented in a dose-dependent manner the effects of 3 mg/kg testosterone propionate (TP) on mouse renal ornithine decarboxylase (acute test) and of 0.5 mg/kg TP on rat prostate weight (chronic test). In these two models, its ED50 was 0.6 and 1 mg/kg, respectively. In the intact rat, when given alone, it inhibited dose-dependently the effect of endogenous androgens on the seminal vesicles (ED50 approximately 1 mg/kg) and prostate (ED50 approximately 3 mg/kg) weights. These results suggest that these new compounds may be useful as specific markers for the androgen receptor as well as for the treatment of androgen-dependent diseases or disorders such as prostate cancer, acne, hirsutism and male pattern baldness.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/metabolismo , Animales , Línea Celular , Cricetinae , Genitales Masculinos/anatomía & histología , Humanos , Imidazoles/metabolismo , Ligandos , Masculino , Ratones , Nitrilos/metabolismo , Tamaño de los Órganos , Conejos , Ratas , Ratas Sprague-Dawley , Globulina de Unión a Hormona Sexual/metabolismo , Especificidad de la Especie , Relación Estructura-Actividad , Testosterona/metabolismoRESUMEN
The synthesis of RU 45196, an 11 beta-substituted 19-norsteroid of the estra-4,9-diene series, incorporating the nitrobenzoxadiazole (NBD) fluorophore, is reported. The highly fluorescent target compound displayed remarkable affinity for both the progesterone and glucocorticoid receptors. The present work demonstrates for the first time that it is indeed possible to design fluorescent steroid conjugates which maintain very high affinities for their cognate receptors and which are potentially useful for mechanistic and diagnostic purposes.
Asunto(s)
Mifepristona/análogos & derivados , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Marcadores de Afinidad/síntesis química , Animales , Diseño de Fármacos , Colorantes Fluorescentes , Mifepristona/síntesis química , Mifepristona/química , Mifepristona/metabolismo , Estructura Molecular , RatasRESUMEN
Flunisolide (FLU), beclomethasone dipropionate (BDP) and its pulmonary metabolites beclomethasone monopropionate (BMP) and beclomethasone (B) were studied in rat for: their relative binding affinity (RBA) for the 5 classes of steroid receptors, their in vitro glucocorticoid activity on rat thymocytes, their in vivo glucocorticoid activity by oral route. These compounds displayed a strong RBA for rat lung, thymus and liver glucocorticoid receptors (FLU > or = BMP > BDP > or = B). They were also shown to have a moderate RBA for both mineralocorticoid and progestin receptors, while being devoid of any binding to androgen and oestrogen receptors. On rat thymocytes FLU exhibited the highest glucocorticoid activity (FLU > B > or = BMP > BDP). In rat oral FLU displayed a strong glucocorticoid activity with a slight first-pass metabolism as opposed to what has been reported in human.