19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a
steroidalprogestin and close
analogue of the
sex hormoneprogesterone, lacking only the C19 methyl group of that molecule. It was first
synthesized in 1944 in the form of a mixture that also included unnatural
stereoisomers (probably C14 (β) and C17 (α)) of progesterone, and this mixture was found to be at least equivalent to
progesterone in terms of progestogenic activity.[1][2][3][4] Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity.[3][4] 19-Norprogesterone was resynthesized in 1951 with an improved method,[3] and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity.[3] In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the
Clauberg assay in rabbits,[5] and at the time of this discovery, 19-norprogesterone was the most potent
progestogen known.[6][7]
Similarly to progesterone, 19-norprogesterone is a potent progestogen and possesses high
affinity for the
mineralocorticoid receptor (MR).[8] However, unlike progesterone, which is an antagonist of the MR, 19-norprogesterone acts as a
partial agonist of the MR and produces
mineralocorticoid effects such as
sodium retention,
polydipsia, and
hypertension in animals.[8] Like progesterone, 19-norprogesterone is very active as a progestogen
parenterally but is only minimally active
orally.[8] A
SARTooltip structure-activity relationship study found that 19-norprogesterone had 47% of the affinity of
aldosterone for the rat MR and that 17α-hydroxylation (17α-hydroxy-19-norprogesterone, or
gestronol) decreased it to 13%.[8] The addition of 6-methylation with formation of a
double bond at this position (
nomegestrol) further decreased the MR affinity to 1.2% of that of aldosterone, and subsequent acetylation of the 17α-hydroxy group (
nomegestrol acetate) nearly abolished it (0.23%).[8]
The discovery of the retained and potentiated progestogenic activity of 19-norsteroids like 19-norprogesterone resulted in the synthesis of
norethisterone, and in turn, the introduction of the first
hormonal contraceptives.[6][7] It was reasoned that since
ethisterone (17α-ethinyltestosterone) is orally active, and since 19-norprogesterone is a very potent progestin parenterally, that 17α-ethynyl-19-nortestosterone (known now as norethisterone or norethindrone) might be a potent, orally active progestin, and indeed, this was found to be the case.[6]
In addition, the testosterone analogue of 19-norprogesterone,
19-nortestosterone (also known as nandrolone), is an
anabolic-androgenic steroid (AAS) and progestogen, and is the
parent compound of a large group of AAS and progestins that includes norethisterone.
^Ehrenstein M (1944). "Investigations on Steroids. VIII. Lower Homologs of Hormones of the Pregnane Series: 10-Nor-11-Desoxy-Corticosterone Acetate and 10-Norprogesterone1". The Journal of Organic Chemistry. 09 (5): 435–456.
doi:
10.1021/jo01187a009.
ISSN0022-3263.
^
abcdMiramontes L, Rosenkranz G, Djerassi C (1951). "Steroids. XXii. The Synthesis of 19-Norprogesterone". Journal of the American Chemical Society. 73 (7): 3540–3541.
doi:
10.1021/ja01151a547.
ISSN0002-7863.
^
abDjerassi C, Miramontes L, Rosenkranz G (1953). "Steroids. XLVIII. 119-Norprogesterone, a Potent Progestational Hormone". Journal of the American Chemical Society. 75 (18): 4440–4442.
doi:
10.1021/ja01114a013.
ISSN0002-7863.
^Tullner WW, Hertz R (March 1953). "High progestational activity of 19-norprogesterone". Endocrinology. 52 (3): 359–361.
doi:
10.1210/endo-52-3-359.
PMID13033848.