Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: A tissue-specific modulator of the glucocorticoid receptor

ALVAREZ, LAUTARO D.; MARTÍ, MARCELO A.; VELEIRO, ADRIANA S.; MISICO, ROSANA I.; ESTRÍN, DARIO A.; PECCI, ADALÍ; BURTON, GERARDO

ChemMedChem

Wiley-VCH

Año: 2008 vol. 3 p. 1869 - 1877

1860-7179

The introduction of a hemisuccinate Group at the 21-position of the passive antiglucocorticoid 21OH-6,19OP leads to a compound (21HS-6,19OP) with a notable activity profile toward the glucocorticoide receptor (GR). In contrast to the parent steroid, 21HS-6,19OP behaves as pure agonist of GR activity in direct transactivation assays. However, the apoptotic effects of 21HS-6,19OP show that the effect depends on cell type: while 21HS-6,19OP is a pure agonist en L929 mouse fibroblast, in thymocytes 21HS-6,19OP has significant antiglucocorticoid activity. This tissue-specific activity makes 21HS-6,19OP a novel selective GR modulator. To investigate the molecular basis of action of 21HS-6,19OP, we carried out molecular dynamics simulation (6ns) of the GR ligand binding domain (LBD) complexed with 21HS-6,19OP. Our results indicate that the hemisuccinate moiety may play a key role in stabilizing the active conformation of the receptor dimerization interface, reverting the changes observed with the antagonist 21OH-6,19OP. Other changes in regions of the GR related to cofactor recruitment (possibly tissue-specific), could explain this particular activity profile.