19-Norprogesterone, also known as19-norpregn-4-ene-3,20-dione, is asteroidalprogestin and closeanalogue of thesex hormoneprogesterone, lacking only the C19 methyl group of that molecule. It was firstsynthesized in 1944 in the form of a mixture that also included unnaturalstereoisomers (probably C14 (β) and C17 (α)) of progesterone, and this mixture was found to be at least equivalent toprogesterone 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 theClauberg assay in rabbits,[5] and at the time of this discovery, 19-norprogesterone was the most potentprogestogen known.[6][7]
Similarly to progesterone, 19-norprogesterone is a potent progestogen and possesses highaffinity for themineralocorticoid receptor (MR).[8] However, unlike progesterone, which is an antagonist of the MR, 19-norprogesterone acts as apartial agonist of the MR and producesmineralocorticoid effects such assodium retention,polydipsia, andhypertension in animals.[8] Like progesterone, 19-norprogesterone is very active as a progestogenparenterally but is only minimally activeorally.[8] ASARTooltip structure-activity relationship study found that 19-norprogesterone had 47% of the affinity ofaldosterone for the rat MR and that 17α-hydroxylation (17α-hydroxy-19-norprogesterone, orgestronol) decreased it to 13%.[8] The addition of 6-methylation with formation of adouble 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 ofnorethisterone, and in turn, the introduction of the firsthormonal contraceptives.[6][7] It was reasoned that sinceethisterone (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 ananabolic-androgenic steroid (AAS) and progestogen, and is theparent 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.
