A. Souque et al., THE MINERALOCORTICOID ACTIVITY OF PROGESTERONE DERIVATIVES DEPENDS ONTHE NATURE OF THE C-18 SUBSTITUENT, Endocrinology, 136(12), 1995, pp. 5651-5658
To investigate the role of the C-18 substituents in the agonist/antago
nist properties of mineralocorticoids, the activities of certain C-18-
substituted progesterone (P) derivatives were examined. These compound
s were characterized by an unsaturated side-chain in the case of 18-vi
nylprogesterone (18VP) and 18-ethynylprogesterone (18EP) and by an eno
ne group in the case of 18-oxo-18-vinylprogesterone (18OVP). P and its
18-substituted derivatives bind to the recombinant human MR (hMR) ove
rexpressed in Sf9 cells with the following hierarchy of affinity: P >
aldosterone > 18VP > 18EP >> 18OVP. Functional cotransfection assays i
n CV-1 cells, using mouse mammary tumor virus promoter as a steroid re
ceptor-inducible DNA target sequence, indicated that the mineralocorti
coid activity depends on the nature of the C-18 substituent. 18VP and
18EP retained the antimineralocorticoid feature of P, with the followi
ng order of activity: P = 18VP > 18EP. The antagonist potency of 18VP
was higher (IC50, similar to 10(-8) M) than that of spironolactone (IC
50, similar to 7 X 10(-8) M), the most widely used aldosterone antagon
ist. Interestingly, introducing an oxo function at C-18 conferred agon
ist mineralocorticoid properties; 18OVP behaves as a full agonist (E(5
0), similar to 10(-7) M) with no antagonist activity. In contrast to w
hat was observed when the three 18-substituted P derivatives acted thr
ough hMR, they retained the agonist feature of P through the human P r
eceptor, with the following order of potency: P > 18VP = 18OVP 18EP. T
he activity of the 18-substituted P derivatives through the human gluc
ocorticoid receptor was only detected at concentrations higher than 10
(-6) M; P and 18VP displayed a partial antagonist activity, whereas 18
OVP had a full agonist activity (ED(50), similar to 2: x 10(-6) M). Th
us, the presence of an oxo group at C-18(18OVP) does not change the ag
onist feature of P through human P receptor, but confers to the ligand
an agonist activity through hMR, suggesting that the C-18 carbonyl gr
oup of aldosterone plays a crucial role in its agonist activity.