Differential effects of the new glucocorticoid receptor antagonist ORG 34517 and RU486 (mifepristone) on glucocorticoid receptor nuclear translocation in the AtT20 cell line.
Glucocorticoid agonists bind to cytoplasmic glucocorticoid receptors (GRs) and subsequently translocate as an agonist-GR complex into the nucleus. In the nucleus the complex regulates the transcription of target genes. A number of GR antagonists (RU486, progesterone, RU40555) have also been shown to induce receptor translocation. These compounds should be regarded as partial agonists. For the nonselective progesterone receptor antagonists, RTI3021-012 and RTI3021-022, it was shown that GR antagonism is possible without the induction of GR translocation. In the present studies, the new GR antagonist, ORG 34517, was investigated for its potential to induce GR translocation and to antagonize corticosterone-induced GR translocation in the AtT20 (mouse pituitary) cell line. ORG 34517 was compared to RU486. In contrast to RU486, ORG 34517 (at doses up to 3 x 10(-7) M) did not induce GR translocation, but was able to block corticosterone (3 x 10(-8) M) induced GR translocation. ORG 34517 can be regarded as a true competitive GR antagonist without partial agonistic activities.
Peeters
B W M M
BW
Department of Clinical Research, N.V. Organon, Oss, The Netherlands. ard.peeters@organon.com
Ruigt
G S F
GS
Craighead
M
M
Kitchener
P
P
D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D002460:Cell Line; D003345:Corticosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology*
D052117:Benzodioxoles; D006727:Hormone Antagonists; C526064:Org 34517; D011965:Receptors, Glucocorticoid; D013256:Steroids; D015735:Mifepristone; D003345:Corticosterone