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5α-Dihydronorethisterone

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5α-Dihydronorethisterone
Clinical data

Other names	5α-DHNET; 5α-Dihydro-NET; Dihydronorethisterone; Dihydronorethindrone; DHNET; 17α-Ethynyl-5α-dihydro-19-nortestosterone; 17α-Ethynyl-5α-estran-17β-ol-3-one; STS-737; NSC-85401; 19-Nor-5α,17α-pregn-20-yn-17-ol-3-one
Identifiers
IUPAC name (5S,8R,9R,10S,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-1,2,4,5,6,7,8,9,10,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-3-one
CAS Number	52-79-9^Y
PubChem CID	63023
ChemSpider	56721
UNII	2DD235DD5X
ChEMBL	ChEMBL3273987
CompTox Dashboard (EPA)	DTXSID30966327
Chemical and physical data
Formula	C₂₀H₂₈O₂
Molar mass	300.442 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CC[C@@H]4[C@@H]3CCC(=O)C4
InChI InChI=1S/C20H28O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,13,15-18,22H,4-12H2,2H3/t13-,15-,16+,17+,18-,19-,20-/m0/s1 Key:OMGILQMNIZWNOK-XDQPPUBWSA-N

5α-Dihydronorethisterone (5α-DHNET, dihydronorethisterone, 17α-ethynyl-5α-dihydro-19-nortestosterone, or 17α-ethynyl-5α-estran-17β-ol-3-one) is a major active metaboliteofnorethisterone (norethindrone).^[1]^[2]^[3]^[4] Norethisterone is a progestin with additional weak androgenic and estrogenic activity.^[1] 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.^[1]^[2]^[3]^[4]

Pharmacology[edit]

Unlike norethisterone which is purely progestogenic, 5α-DHNET has been found to possess both progestogenic and marked antiprogestogenic activity, showing a profile of progestogenic activity like that of a selective progesterone receptor modulator (SPRM).^[4] Moreover, the affinity of 5α-DHNET for the progesterone receptor (PR) is greatly reduced relative to that of norethisterone at only 25% of that of progesterone (versus 150% for norethisterone).^[1]

5α-DHNET shows higher affinity for the androgen receptor (AR) compared to norethisterone with approximately 27% of the affinity of the potent androgen metribolone (versus 15% for norethisterone).^[1] However, although 5α-DHNET has higher affinity for the AR than does norethisterone, it has significantly diminished and in fact almost abolished androgenic activity in comparison to norethisterone in rodent bioassays.^[2]^[5] Similar findings were observed for ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays.^[5] As such, it appears that the C17α ethynyl group of norethisterone is responsible for its loss of androgenicity upon 5α-reduction.^[5] Instead of androgenic activity, 5α-DHNET has been reported to possess some antiandrogenic activity.^[6]

Norethisterone and 5α-DHNET have been found to act as weak irreversible aromatase inhibitors (K_i = 1.7 μM and 9.0 μM, respectively).^[7] However, the concentrations required are probably too high to be clinically relevant at typical dosages of norethisterone.^[1] 5α-DHNET specifically has been assessed and found to be selective in its inhibitionofaromatase, and does not affect other steroidogenesis enzymes such as cholesterol side-chain cleavage enzyme (P450scc), 17α-hydroxylase/17,20-lyase, 21-hydroxylase, or 11β-hydroxylase.^[7] Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5α-DHNET has been proposed as a potential therapeutic agent in the treatment of estrogen receptor (ER)-positive breast cancer.^[7]

v

t

e
Relative affinities (%) of norethisterone, metabolites, and prodrugs
Compound	Type^a	PRTooltip Progesterone receptor	ARTooltip Androgen receptor	ERTooltip Estrogen receptor	GRTooltip Glucocorticoid receptor	MRTooltip Mineralocorticoid receptor	SHBGTooltip Sex hormone-binding globulin	CBGTooltip Corticosteroid binding globulin
Norethisterone	–	67–75	15	0	0–1	0–3	16	0
5α-Dihydronorethisterone	Metabolite	25	27	0	0	?	?	?
3α,5α-Tetrahydronorethisterone	Metabolite	1	0	0–1	0	?	?	?
3α,5β-Tetrahydronorethisterone	Metabolite	?	0	0	?	?	?	?
3β,5α-Tetrahydronorethisterone	Metabolite	1	0	0–8	0	?	?	?
Ethinylestradiol	Metabolite	15–25	1–3	112	1–3	0	0.18	0
Norethisterone acetate	Prodrug	20	5	1	0	0	?	?
Norethisterone enanthate	Prodrug	?	?	?	?	?	?	?
Noretynodrel	Prodrug	6	0	2	0	0	0	0
Etynodiol	Prodrug	1	0	11–18	0	?	?	?
Etynodiol diacetate	Prodrug	1	0	0	0	0	?	?
Lynestrenol	Prodrug	1	1	3	0	0	?	?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Footnotes: ^a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

References[edit]

^ ^a ^b ^c ^d ^e ^f Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.

^ ^a ^b ^c Fragkaki AG, Angelis YS, Koupparis M, Tsantili-Kakoulidou A, Kokotos G, Georgakopoulos C (February 2009). "Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure". Steroids. 74 (2): 172–197. doi:10.1016/j.steroids.2008.10.016. PMID 19028512. S2CID 41356223. Many synthetic steroids with high myotrophic activity exhibit myotrophic–androgenic dissociation, since, due to changes introduced in the structure of ring A, they will probably not be substrates for the 5α-reductases [85]. 5α-Reduction does not always amplify the androgenic potency in spite of high RBA of androgens to the AR. This is the case for norethisterone (Fig. 1, 34), a synthetic 19-nor-17α-ethynyl testosterone derivative, which also undergoes enzyme-mediated 5α-reduction and exerts potent androgenic effects in target organs. 5α-Reduced norethisterone displays a higher AR binding but shows a significantly lower androgenic potency than unchanged norethisterone [102,103].

^ ^a ^b Fedotov VP, Gudoshnikov VI, Kurishko AI (1988). "[Effect of synthetic analogs of the sex steroid hormones on the secretory and proliferative activity of the adenohypophysis in vivo and in vitro in rats]". Farmakologiia I Toksikologiia (in Russian). 51 (5): 57–61. PMID 3208885.

^ ^a ^b ^c Chu YH, Li QA, Zhao ZF, Zhou YP, Cao DC (June 1985). "[Antiprogestational action of 5 alpha-dihydronorethisterone]". Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica (in Chinese). 6 (2): 125–129. PMID 2934946.

^ ^a ^b ^c Lemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G (January 1997). "5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency". The Journal of Steroid Biochemistry and Molecular Biology. 60 (1–2): 121–129. doi:10.1016/s0960-0760(96)00172-0. PMID 9182866. S2CID 33771349.

^ Kamischke A, Nieschlag E (January 2004). "Progress towards hormonal male contraception". Trends in Pharmacological Sciences. 25 (1): 49–57. doi:10.1016/j.tips.2003.11.009. PMID 14723979.

^ ^a ^b ^c Yamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H (June 1994). "Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes". European Journal of Endocrinology. 130 (6): 634–640. doi:10.1530/eje.0.1300634. PMID 8205267.