Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16α,17α-acetal-substituted glucocorticoids

E. Dahlberg, A. Thalen, R. Brattsand, Jan-Ake Gustafsson, U. Johansson, K. Roempke, T. Saartok

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The affinity of the glucocorticoid receptor in rat skeletal muscle of some glucocorticoids with a new type of 16α,17α-acetal substituent has been estimated and correlated to the glucocorticoid activities in three in vivo systems in rats. Budesonide (an approximately 1:1 mixture of the C(22) epimers of 11β,21-dihydroxy-16α,17α-[22R,S)-propylmethylenedioxy]-pregna-1,4-diene- 3,20-dione) and the isolated (22R)- and (22S)-epimers bound to the same binding site as the potent glucocorticoids dexamethasone (DEX) or triamcinolone 16*17*-acetonide (TA), but with even higher affinity than DEX or TA, despite the lack of 9α-fluoro atom in budesonide and its epimers. The (22R)-epimer was twice as active as the (22S)-epimer, 4 times more active that TA, and 14 times more active the DEX. The introduction of a 9α-fluoro atom slightly decreased the binding affinity of the (22R)-epimer of budesonide, in contrast to the positive effects of 9α-fluorination of, e.g., 16α,17β-acetonides. The negative influence of 9α-fluorination of the (22R)-epimer was partially reversed in the 6α,9α-fluorination (22R)-epimer. Nevertheless, the fluorinated compounds were more active than DEX and TA (8 and 11 times more active than DEX, and 2 and 3 times more active than TA, in case of the 9α-fluoro- and 6α,9α-difluoro-derivatives of the (22R)-epimer, respectively). Budesonide is metabolized mainly to 16α-hydroxyprednisolone (11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione) and 6β-hydroxy-budesonide. Both metabolites were very weak competitors for the ligand-binding sites on the receptor (3% and 6% of the affinity of DEX, respectively). The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared (r = 0.98; R = 0.98), which supports the contention that in vitro tests for the receptor affinity are useful when screening for agonists among steroids with the present type of structures. The results on receptor-ligand interaction are in accordance with X-ray crystallographic data available for some steroids.

Original languageEnglish (US)
Pages (from-to)70-78
Number of pages9
JournalMolecular Pharmacology
Issue number1
StatePublished - Mar 15 1984

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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