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5α-Dihydroprogesterone
Names
IUPAC name
5α-Pregnane-3,20-dione
Systematic IUPAC name
(1S ,3aS ,3bR ,5aS ,9aS ,9bS ,11aS )-1-Acetyl-9a,11a-dimethylhexadecahydro-7H -cyclopenta[a ]phenanthren-7-one
Other names
Allopregnanedione
Identifiers
ChEBI
ChemSpider
ECHA InfoCard
100.008.453
UNII
InChI=1S/C21H32O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h14,16-19H,4-12H2,1-3H3/t14-,16-,17+,18-,19-,20-,21+/m0/s1
Key: XMRPGKVKISIQBV-BJMCWZGWSA-N
CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CCC(=O)C4)C)C
Properties
C 21 H 32 O 2
Molar mass
316.485 g·mol−1
Except where otherwise noted, data are given for materials in their
standard state (at 25 °C [77 °F], 100 kPa).
Chemical compound
5α-Dihydroprogesterone (5α-DHP , allopregnanedione ,
[1] or 5α-pregnane-3,20-dione ) is an
endogenous
progestogen and
neurosteroid that is
synthesized from
progesterone .
[2]
[3] It is also an
intermediate in the synthesis of
allopregnanolone and
isopregnanolone from progesterone.
5α-DHP is metabolized by the
aldo-keto reductases (AKRs)
AKR1C1 ,
AKR1C2 , and
AKR1C4 with high catalytic efficiency.
[4] AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one while AKR1C2 preferentially forms allopregnanolone.
[4] Similarly AKR1C1 reduces and consequently inactivates allopregnanolone into
5α-pregnane-3α,20α-diol .
[4] In contrast to the other AKRs,
AKR1C3 has low catalytic efficiency for reduction of 5α-DHP.
[4] These AKRs are highly expressed in the human
liver and
mammary gland but have relatively modest expression in the human
brain and
uterus .
[5]
5α-DHP is an
agonist of the
progesterone receptor and a
positive allosteric modulator of the
GABAA receptor (albeit with an
affinity for this
receptor that is regarded as relatively low (in comparison to 3α-hydroxylated progesterone
metabolites such as allopregnanolone and
pregnanolone )).
[2]
[3]
[6]
[7] It has also been found to act as a
negative allosteric modulator of the
GABAA -rho receptor .
[8] The steroid has been found to possess 82% of the affinity of progesterone for the progesterone receptor in
rhesus monkey
uterus .
[9] 5α-Dihydroprogesterone has been said to possess about 33% of the relative
progestogenic
potency of progesterone.
[10] In addition, it is a weak agonist of the
pregnane X receptor (PXR) (
EC50 >10,000 μM), with approximately six-fold lower potency relative to its 5β-isomer,
5β-dihydroprogesterone .
[11]
Allopregnanolone is transformed back into 5α-DHP by
3α-hydroxysteroid oxidoreductase , and conversion of allopregnanolone into 5α-DHP is responsible for the progestogenic activity of allopregnanolone.
[6]
[12]
[13] 5α-DHP, via the progesterone receptor, and allopregnanolone, via the
GABAA receptor , act together to induce
lordosis in animals.
[12]
[13] A study found that 41% of allopregnanolone that was administered via injection was transformed into 5α-DHP in the rat brain.
[12]
Levels of 5α-DHP have been quantified.
[14]
^ Finn, Deborah A.; Purdy, Robert H. (2007). "Neuroactive Steroids in Anxiety and Stress". Handbook of Contemporary Neuropharmacology .
doi :
10.1002/9780470101001.hcn026 .
ISBN
978-0470101001 .
^
a
b Mellon SH (October 2007).
"Neurosteroid regulation of central nervous system development" . Pharmacol. Ther . 116 (1): 107–24.
doi :
10.1016/j.pharmthera.2007.04.011 .
PMC
2386997 .
PMID
17651807 .
^
a
b Guidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E (November 2001). "The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders". Brain Res. Brain Res. Rev . 37 (1–3): 110–5.
doi :
10.1016/s0165-0173(01)00129-1 .
PMID
11744079 .
S2CID
22202599 .
^
a
b
c
d Rižner TL, Penning TM (January 2014).
"Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism" . Steroids . 79 : 49–63.
doi :
10.1016/j.steroids.2013.10.012 .
PMC
3870468 .
PMID
24189185 .
^ Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K (October 2000).
"Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones" . Biochem. J . 351 (Pt 1): 67–77.
doi :
10.1042/bj3510067 .
PMC
1221336 .
PMID
10998348 .
^
a
b Rupprecht R, Reul JM, Trapp T, et al. (September 1993). "Progesterone receptor-mediated effects of neuroactive steroids". Neuron . 11 (3): 523–30.
doi :
10.1016/0896-6273(93)90156-l .
PMID
8398145 .
S2CID
11205767 .
^ Ocvirk, Rok; Pearson Murphy, Beverley E.; Franklin, Keith B.J.; Abbott, Frances V. (2008). "Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test". Pain . 138 (2): 402–409.
doi :
10.1016/j.pain.2008.01.019 .
ISSN
0304-3959 .
PMID
18343034 .
S2CID
32370572 .
^ Johnston GA (2002).
"Medicinal chemistry and molecular pharmacology of GABA(C) receptors" (PDF) . Curr Top Med Chem . 2 (8): 903–13.
doi :
10.2174/1568026023393453 .
PMID
12171579 . Archived from
the original (PDF) on December 26, 2010.
^ Illingworth DV, Elsner C, De Groot K, Flickinger GL, Mikhail G (February 1977). "A specific progesterone receptor of myometrial cytosol from the rhesus monkey". J. Steroid Biochem . 8 (2): 157–60.
doi :
10.1016/0022-4731(77)90040-1 .
PMID
405534 .
^ Rogerio A. Lobo; Jennifer Kelsey; Robert Marcus (22 May 2000).
Menopause: Biology and Pathobiology . Academic Press. pp. 433–.
ISBN
978-0-08-053620-0 .
^ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998).
"The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions" . J. Clin. Invest . 102 (5): 1016–23.
doi :
10.1172/JCI3703 .
PMC
508967 .
PMID
9727070 .
^
a
b
c Beyer C, González-Flores O, Ramírez-Orduña JM, González-Mariscal G (February 1999). "Indomethacin inhibits lordosis induced by ring A-reduced progestins: possible role of 3alpha-oxoreduction in progestin-facilitated lordosis". Horm Behav . 35 (1): 1–8.
doi :
10.1006/hbeh.1998.1457 .
PMID
10049597 .
S2CID
11520064 .
^
a
b Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G (November 1995). "Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor". Physiol. Behav . 58 (5): 985–93.
doi :
10.1016/0031-9384(95)00141-5 .
PMID
8577898 .
S2CID
25967801 .
^ Trabert B, Falk RT, Stanczyk FZ, McGlynn KA, Brinton LA, Xu X (September 2015).
"Reproducibility of an assay to measure serum progesterone metabolites that may be related to breast cancer risk using liquid chromatography-tandem mass spectrometry" . Horm Mol Biol Clin Investig . 23 (3): 79–84.
doi :
10.1515/hmbci-2015-0026 .
PMC
4966666 .
PMID
26353176 .
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor
Positive modulators (abridged; see
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α-EMTBL
Alcohols (e.g.,
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Kava constituents (e.g.,
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Volatiles /
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Negative modulators:
1,3M1B
3M2B
11-Ketoprogesterone
17-Phenylandrostenol
α3IA
α5IA (LS-193,268)
β-CCB
β-CCE
β-CCM
β-CCP
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Anabolic steroids
Amiloride
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FG-7142 (ZK-31906)
Fiproles (e.g.,
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Fluoroquinolones (e.g.,
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Isopregnanolone (sepranolone)
L-655,708
Laudanosine
Lindane
MaxiPost
Morphine
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MRK-016
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PWZ-029
Radequinil
Ro 15-4513
Ro 19-4603
RO4882224
RO4938581
Sarmazenil
SCS
Suritozole
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TETS
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U-93631
Zinc
ZK-93426
GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor
Alcohols
Barbiturates
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Imidazoles
Kava constituents
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Nonbenzodiazepines
Phenols
Piperidinediones
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Quinazolinones
Volatiles /
gases Others/unsorted
3-Hydroxybutanal
α-EMTBL
AA-29504
Alogabat
Avermectins (e.g.,
ivermectin )
Bromide compounds (e.g.,
lithium bromide ,
potassium bromide ,
sodium bromide )
Carbamazepine
Chloralose
Chlormezanone
Clomethiazole
Darigabat
DEABL
Deuterated etifoxine
Dihydroergolines (e.g.,
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dihydroergosine ,
dihydroergotamine ,
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DS2
Efavirenz
Etazepine
Etifoxine
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flufenamic acid ,
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niflumic acid ,
tolfenamic acid )
Fluoxetine
Flupirtine
Hopantenic acid
KRM-II-81
Lanthanum
Lavender oil
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Org 25,435
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Topiramate
Valerian constituents (e.g.,
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PR Tooltip Progesterone receptor
Agonists
Testosterone derivatives: Progestins:
6,6-Difluoronorethisterone
6,6-Difluoronorethisterone acetate
17α-Allyl-19-nortestosterone
Allylestrenol
Altrenogest
Chloroethynylnorgestrel
Cingestol
Danazol
Desogestrel
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Ethinylandrostenediol
Ethisterone
Ethynerone
Etonogestrel
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Etynodiol diacetate
Gestodene
Gestrinone
Levonorgestrel
Levonorgestrel esters (e.g.,
levonorgestrel butanoate )
Lynestrenol
Lynestrenol phenylpropionate
Metynodiol
Metynodiol diacetate
Norelgestromin
Norethisterone (norethindrone)
Norethisterone esters (e.g.,
norethisterone acetate ,
norethisterone enanthate )
Noretynodrel
Norgesterone
Norgestimate
Norgestrel
Norgestrienone
Norvinisterone
Oxendolone
Quingestanol
Quingestanol acetate
Tibolone
Tigestol
Tosagestin ; Anabolic–androgenic steroids:
11β-Methyl-19-nortestosterone
11β-Methyl-19-nortestosterone dodecylcarbonate
19-Nor-5-androstenediol
19-Nor-5-androstenedione
19-Nordehydroepiandrosterone
Bolandiol
Bolandiol dipropionate
Bolandione
Dimethisterone
Dienedione
Dienolone
Dimethandrolone
Dimethandrolone buciclate
Dimethandrolone dodecylcarbonate
Dimethandrolone undecanoate
Dimethyldienolone
Dimethyltrienolone
Ethyldienolone
Ethylestrenol (ethylnandrol)
Methyldienolone
Metribolone (R-1881)
Methoxydienone (methoxygonadiene)
Mibolerone
Nandrolone
Nandrolone esters (e.g.,
nandrolone decanoate ,
nandrolone phenylpropionate )
Norethandrolone
Normethandrone (methylestrenolone, normethandrolone, normethisterone)
RU-2309
Tetrahydrogestrinone
Trenbolone (trienolone)
Trenbolone esters (e.g.,
trenbolone acetate ,
trenbolone enanthate )
Trendione
Trestolone
Trestolone acetate
Mixed (
SPRMs Tooltip Selective progesterone receptor modulators ) Antagonists
mPR Tooltip Membrane progesterone receptor (
PAQR Tooltip Progestin and adipoQ receptor )
CAR Tooltip Constitutive androstane receptor
PXR Tooltip Pregnane X receptor