RESUMEN
The effect of several new dihydroepiandrosterone ester derivatives A2-A6 was demonstrated using female cycling mice, which were synchronized for estrus with luteinizing hormone-releasing hormone (LHRH) and injected with the steroids. The binding to the progesterone receptor (PR), was obtained from the cytosol of uteri from adult estrogen-primed rabbits. A1 binds to the PR and inhibited the ovulation in cycling mice stimulated with LHRH. The activity of the endometrium and mammary glands in these mice was markedly reduced as compared to the control. A2, A4, and A5 were not active; nevertheless, A3 binds to the PR with high affinity. However, this steroid did not produce any effect as compared to that observed for the control in the endometrial and mammary glands. A6 binds to the PR with the highest affinity and induces a synergistic activity with progesterone in these tissues. Furthermore, A6 inhibited the ovulation in the same manner as A1. These results suggested that A1 and A6 are blocking the gonadotropin secretion. A1 inhibited the conversion of progesterone to 5α-progesterone. As a result of this, a blockage of the ductal and alveolar epithelial cell proliferation in the mammary and endometrial glands, which depends on 5α-progesterone, was also observed.
Asunto(s)
Androstenos/farmacología , Ciclo Estral/fisiología , Ovulación/efectos de los fármacos , Receptores de Progesterona/metabolismo , Androstenos/síntesis química , Androstenos/química , Animales , Proliferación Celular/efectos de los fármacos , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Masculino , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Ratones , Persona de Mediana Edad , Progesterona/metabolismo , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Conejos , Relación Estructura-ActividadRESUMEN
The aim of these studies was to synthesize twelve ester derivatives of dehydroepiandrosterone with therapeutic potential. The effect of 1-12 was demonstrated in the flank organs of gonadectomized hamsters treated with testosterone and the synthesized steroids. In vitro studies were carried out determining the IC50 values for the inhibition of the activity of 5α-reductase type 1 and 2, which are present in rat liver and human prostate respectively. The binding of 1-12 to the androgen receptors (AR) was determined using rat's prostate cytosol. Steroids 1-12 containing different substituents in the phenyl group of the ester moiety in C-3 reduced the flank organs and inhibited the activity of 5α-R type 1; however only steroids 1 and 2 inhibited 5α-R type 2. 1-12 did not bind to the AR. The modification of one atom of the substituents in the phenyl group of the ester moiety in C-3 changed their biological potency (IC50).