21-Hydroxy-6,19-oxidoprogesterone: A Novel Synthetic Steroid with Specific Antiglucocorticoid Properties in the Rat

Abstract

In the rat, the conformationally highly bent steroid 21-hydroxy-6, 19-oxidoprogesterone efficiently displaces [3H]corticosterone from thymus-glucocorticoid receptors and blocks type II receptors in kidney cytosols but competes with neither [3H]aldosterone for kidney-mineralocorticoid receptors nor [3H]progesterone for uterus-progesterone receptors. It evokes Na+ retention only at very high doses (approximately 100 microg/100 g of rat weight) and is unable to induce tyrosine aminotransferase or to increase glycogen deposits in rat liver. When coincubated with corticosterone or dexamethasone, 2.5 microM 21OH-6OP inhibits 80% of tyrosine aminotransferase induction. It may therefore be used experimentally as an antiglucocorticoid virtually lacking mineralocorticoid or glucocorticoid properties as well as affinity for mineralocorticoid or progesterone receptors.

Differential interaction of RU486 with the progesterone and glucocorticoid receptors

“…For example, spironolactone has been used for some time as an anti-mineralocorticoid agent, but 10% of patients discontinue the drug because of side effects resulting from its anti-androgen and anti-progestin activities; a new specific anti-mineralocorticoid, eplerenone, has only recently become available (Delyani et al 2001, Zillich & Carter 2002, Stier 2003. The only presently available anti-glucocorticoid agent is RU486, a drug, which is far better known for its anti-progestin activities (Vicent et al 1997). The challenge in designing specific steroid receptor antagonists stems, in part, from the evolutionary conserved structures of the ligandbinding domains (LBDs) of these receptors.…”

The rigid steroid 21-hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a dissociated glucocorticoid receptor modulator potentially useful as a novel coadjuvant in breast cancer chemotherapy

“…Moreover, when 21OH-6,19OP was co-incubated with corticosterone or DEX, it antagonized the transactivation pathway [14,16]. 21OH-6,19OP also behaves as a strong anti-glucocorticoid, blocking DEX-dependent apoptosis in thymocytes [17].…”

“…Upon GR binding, 19OP activates translocation of the receptor to the nucleus and its dimerization [15]. This rigid steroid has the potential function of a dissociated GC since it inhibits Rel A and activator protein 1 (AP-1) dependent gene expression in BHK and Cos-1 cells [15][16] but it is unable to induce tyrosine aminotransferase or to increase glycogen deposits in rat liver [14] and MMTV-LUC reporter gene expression in L929 fibroblasts [17] and in Cos-1 cells transfected with the GR receptor [16].…”

“…One of these compounds, 21OH-6,19OP, is a synthetic conformationally rigid highly bent pregnane steroid that lacks the bulky substituent at C-11 found in active antagonists of the GR [14]. 19OP behaves as a selective GC since it efficiently displaces [ 3 H]corticosterone from thymus-GR but neither competes with [ 3 H]aldosterone binding to kidney-mineralocorticoid receptor nor with [ 3 H]progesterone binding to uterus-progesterone receptors [14]. Upon GR binding, 19OP activates translocation of the receptor to the nucleus and its dimerization [15].…”

“…de Buenos Aires, Argentina). 21OH-6,19OP was prepared as previously described [14,19]. For in vitro experiments, LPS and DEX were dissolved in sterile water and ethanol, respectively, and 21OH-6,19OP and paclitaxel, in DMSO; compounds were prepared as 1000X stock solution and store at -20°C.…”