title: Hemisuccinate of 21-hydroxy-6,19-epoxyprogesterone: a tissue-specific modulator of the glucocorticoid receptor.
abstract: 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 glucocorticoid receptor (GR). In contrast to the parent steroid, 21HS-6,19OP behaves as a 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 in L929 mouse fibroblasts, in thymocytes 21HS-6,19OP had 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 simulations (6 ns) 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.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EGA Buenos Aires, Argentina.
authors.forename: Lautaro D
authors.initials: LD
authors.lastname: Alvarez
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Martí
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.forename: Rosana I
authors.initials: RI
authors.lastname: Misico
authors.forename: Darío A
authors.initials: DA
authors.lastname: Estrin
authors.forename: Adalí
authors.initials: A
authors.lastname: Pecci
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D019281:Dimerization; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D011374:Progesterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011372:Progestins / Q000737:chemistry / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C108699:21-hydroxy-6,19-oxidoprogesterone; C534953:21-succinyloxy-6,19-epoxyprogesterone; D011372:Progestins; D011965:Receptors, Glucocorticoid; D011374:Progesterone