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| 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 |
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| Formula | C20H28O2 |
| Molar mass | 300.442 g·mol−1 |
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5α-Dihydronorethisterone (5α-DHNET,dihydronorethisterone,17α-ethynyl-5α-dihydro-19-nortestosterone, or17α-ethynyl-5α-estran-17β-ol-3-one) is a majoractive metabolite ofnorethisterone (norethindrone).[1][2][3][4] Norethisterone is aprogestin with additional weakandrogenic andestrogenic activity.[1] 5α-DHNET is formed from norethisterone by5α-reductase in theliver and othertissues.[1][2][3][4]
Unlike norethisterone which is purely progestogenic, 5α-DHNET has been found to possess bothprogestogenic and markedantiprogestogenic activity, showing a profile of progestogenic activity like that of aselective progesterone receptor modulator (SPRM).[4] Moreover, theaffinity of 5α-DHNET for theprogesterone receptor (PR) is greatly reduced relative to that of norethisterone at only 25% of that ofprogesterone (versus 150% for norethisterone).[1]
5α-DHNET shows higher affinity for theandrogen receptor (AR) compared to norethisterone with approximately 27% of the affinity of thepotentandrogenmetribolone (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 rodentbioassays.[2][5] Similar findings were observed forethisterone (17α-ethynyltestosterone) and its5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency oftestosterone andnandrolone (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 someantiandrogenic activity.[6]
Norethisterone and 5α-DHNET have been found to act as weakirreversiblearomatase inhibitors (Ki = 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 beselective in itsinhibition ofaromatase, and does not affect othersteroidogenesisenzymes such ascholesterol side-chain cleavage enzyme (P450scc),17α-hydroxylase/17,20-lyase,21-hydroxylase, or11β-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 ofestrogen receptor (ER)-positivebreast cancer.[7]
| Compound | Typea | 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 (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Footnotes:a =Active or inactivemetabolite,prodrug, or neither of norethisterone.Sources: See template. | ||||||||
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].
