Structure-activity and structure-affinity relationships of 19-nor-progesterone derivatives in rat uterus.
19-nor-progesterone (19NP) is a potent progestagen which possesses a high affinity for the progesterone receptor (PgR). In contrast, 17 alpha-hydroxylated-progesterone (17OHP) shows no hormonal activity and does not compete with progesterone (P) for the PgR. The aim of the present work was to analyse in parallel the structure-affinity and the structure-activity relationships for new molecules obtained by modifications of 19NP and 17OHP. The attachment of a 17 alpha-hydroxyl group on 19NP led to a dramatic decrease in both affinity and activity for the end-product, 17 alpha-hydroxylated-19-nor-progesterone (17OH-19NP). The further addition of a methyl group combined with the formation of a double-bound at C6 on 17OH-19NP results in nomegestrol (NOM), the relative affinity of which remained low. Negligible activity was also associated with this affinity in comparison to the parent 19NP. Strikingly, the protection of the free 17 alpha-hydroxyl group of NOM by an acetate led to a potent progestin with high affinity for PgR. It is concluded that the sum of the modifications brought into the 17OHP-19NP molecule reestablishes both affinity and activity of the original 19NP molecule. The same conclusion holds if P is considered as the parent compound, as already stated in the literature.
Botella
J
J
Laboratoires Theramex, Université de Nice Sophia Antipolis, Nice, France.
Duc
I
I
Delansorne
R
R
Paris
J
J
Lahlou
B
B
D019326:17-alpha-Hydroxyprogesterone; D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006908:Hydroxyprogesterones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008535:Megestrol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D009653:Norprogesterones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010052:Ovariectomy; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D006908:Hydroxyprogesterones; D009653:Norprogesterones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C047637:nomegestrol; C030703:19-norprogesterone; D019326:17-alpha-Hydroxyprogesterone; D008535:Megestrol