17β- Carboxamide steroids are a new class of glucocorticoid antagonists

Abstract

GLUCOCORTICOID hormones exert many of their effects by modifying the activity of certain enzymes in target tissues, probably as a result of alterations in gene expression¹. Experimental models have been developed in which enzyme induction by various steroids correlates well with their anti-inflammatory, thymolytic and glycopexic properties. This is the case for tyrosine transaminase in cultured rat hepatoma (HTC) cells^2,3. Studies in this system showed that, in addition to glucocorticoid agonists, partial agonists and antagonists could be identified⁴. The latter compete with agonists for binding to the intracellular glucocorticoid receptor but do not trigger the glucocorticoid effect⁵. Compounds which specifically antagonise glucocorticoid action at the target cell would be useful for the treatment of certain diseases characterised by excessive production of gluco-corticoids¹ and for further studying the molecular mechanism of action of these hormones. However, unlike anti-androgens and anti-oestrogens⁶, the only known glucocorticoid anatagonists are natural steroid hormones (such as progesterone and testosterone) or their analogues, which interact with their own receptors and plasma binding proteins and are therefore not very specific. We report here that new derivatives of dexamethasone, a specific glucocorticoid agonist which does not bind to rat or human plasma transcortin⁵, can block the induction of tyrosine transaminase in HTC cells.