The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: Implicationsfor the development of dissociated antiprogestins
Bl. Wagner et al., The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: Implicationsfor the development of dissociated antiprogestins, ENDOCRINOL, 140(3), 1999, pp. 1449-1458
We have identified two novel compounds (RTI 3021-012 and RTI 3021-022) that
demonstrate similar affinities for human progesterone receptor (PR) and di
splay equivalent antiprogestenic activity. As with most antiprogestins, suc
h as RU486, RTI 3021-012, and RTI 3021-022 also bind to the glucocorticoid
receptor (GR) with high affinity. Unexpectedly, when compared with RU486, t
he RTI antagonists manifest significantly less GR antagonist activity. This
finding indicates that, with respect to antiglucocorticoid function, recep
tor binding affinity is not a good predictor of biological activity. We hav
e determined that the lack of a clear correlation between the GR binding af
finity of the RTI compounds and their antagonist activity reflects the uniq
ue manner in which they modulate GR signaling. Previously, we proposed a tw
o step "active inhibition" model to explain steroid receptor antagonism: 1)
competitive inhibition of agonist binding; and 2) competition of the antag
onist bound receptor with that activated by agonists for DNA response eleme
nts within target gene promoters. Accordingly, we observed that RU486, RTI
3021-012, and RTI 302-1022, when assayed for PR antagonist activity, accomp
lished both of these steps. Thus, all three compounds are "active antagonis
ts" of PR function. When assayed on GR, however, RU486 alone functioned as
an active antagonist. RTI 3021-012 and RTI 3021-022, on the other hand, fun
ctioned solely as "competitive antagonists" since they were capable of high
affinity GR binding, but the resulting ligand receptor complex was unable
to bind DNA. These results have important pharmaceutical implications suppo
rting the use of mechanism based approaches to identify nuclear receptor mo
dulators. Of equal importance, RTI 3021-012 and RTI 3021-022 are two new an
tiprogestins that may have clinical utility and are likely to be useful as
research reagents with which to separate the effects of antiprogestins and
antiglucocorticoids in physiological systems.