Extinction of mineralocorticoid effects in 19-norprogesterone derivatives: structure-activity relationships

19-Norprogesterone (19-NOR-P) is a potent progestagen in mammals by s.c. injection, but is almost inactive when given p.o. In the rat, 19-NOR-P also shows marked salt-retaining and hypertensive effects, consistent with its high affinity for mineralocorticoid receptors (MR). We synthetized recently some p.o. active 19-NOR-P derivatives, and have examined the extent to which the structural changes made on the parent compound can modify the affinity for MR and the salt-retaining potency. Compared with aldosterone, 19-NOR-P has a 47% affinity for rat renal cytosolic MR, decreasing to 13% with alpha-hydroxylation on C-17 (17 alpha-OH-19-NOR-P). The addition of a methyl group combined with the formation of a double bond at C-6 led to nomegestrol, the relative affinity of which was 1.2%. Binding was almost abolished completely (0.23%) by acetylation of the 17 alpha-OH group (nomegestrol-acetate). A single s.c. injection of 19-NOR-P, 20 micrograms/animal, induced a marked decline of [Na+]/[K+] ratio in urine of adrenalectomized male rats. The antinatriuretic effect was still observed after a 11-day period of daily administrations of the same dosage. 17 alpha-OH-19-NOR-P decreased the [Na+]/[K+] ratio only at a high p.o. dose (2500 micrograms/animal). NOM-Ac did not affect the [Na+]/[K+] ratio after a single s.c. or p.o. administration, but increased it at the end of a 11-day p.o. treatment. Thus, the chemical modifications that lead to potent p.o. active progestins derived from 19-NOR-P induce stepwise reductions in the affinity for MR and of the mineralocorticoid effects of the parent compound.