Glucocorticoid activity of 11 beta,17 beta-dihydroxy-21-methyl-17 alpha-pregna-1,4,6-trien-20-yn-3-one (RU-26988).

Natural and most synthetic glucocorticoids have either a 17 alpha-21-dihydroxy-20-keto or 21-hydroxy-20-keto side chain. Recently a group of 17 alpha-alkynyl steroids which lacks this side chain has been described to have glucocorticoid activity. We have studied the ability of RU-26988 (11 beta,17 beta-dihydroxy-21-methyl-17 alpha-pregna-1, 4,6, trien-20-yn-3-one) to interact with the glucocorticoid receptor and its biological activity in both in vitro and in vivo bioassays. RU-26988 was as active as dexamethasone in competing with [3H] dexamethasone for the liver cytosol receptor, while it had 120% the ability of dexamethasone to compete with [3H] dexamethasone for the HTC cell receptors. RU-26988 had 20% and dexamethasone 14% of the competing ability of triamcinolone acetonide for [3H] triamcinolone acetonide binding to the L-929 fibroblast receptor system. The in vitro glucocorticoid activity as measured by the induction of tyrosine aminotransferase (TAT) in HTC cells by RU-26988 was only 30% that of dexamethasone and the maximal activity was also reduced, suggesting that it behaves as a suboptimal inducer in this system. In the L-929 fibroblast it had 32% the activity of dexamethasone but the maximal inhibition by the two was similar. RU-26988 had only 3.2% the activity of dexamethasone in in vivo rat bioassays (induction of TAT or glycogen deposition in the liver). These data supplement other reports that RU-26988 might be a promising glucocorticoid for topical use where it behaves as a powerful agonist, but not for systemic use, where it is considerably weaker.