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.
D000732:Androstanols / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay; D002460:Cell Line; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000096:biosynthesis*
D000732:Androstanols; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; C038341:RU 26988; D003907:Dexamethasone; D014444:Tyrosine Transaminase