:5α-Dihydroprogesterone

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| ImageFile=5-alpha-dihydroprogesterone.png

| ImageClass = skin-invert-image

| ImageSize=200px

| ImageAlt = Skeletal formula of 5α-dihydroprogesterone

| ImageFile1 = 5alpha-Dihydroprogesterone 3D ball.png

| ImageAlt1 = Ball-and-stick model of the 5α-dihydroprogesterone molecule

| IUPACName=5α-Pregnane-3,20-dione

| SystematicName=(1S,3aS,3bR,5aS,9aS,9bS,11aS)-1-Acetyl-9a,11a-dimethylhexadecahydro-7H-cyclopenta[a]phenanthren-7-one

| OtherNames=Allopregnanedione

|Section1={{Chembox Identifiers

| CASNo=566-65-4

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 98G4S1OH0Z

| PubChem = 92810

| ChemSpiderID = 83782

| StdInChI = 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

| StdInChIKey = XMRPGKVKISIQBV-BJMCWZGWSA-N

| ChEBI = 28952

| SMILES=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

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|Section2={{Chembox Properties

| C=21 | H=32 | O=2

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|Section3={{Chembox Hazards

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5α-Dihydroprogesterone (5α-DHP, allopregnanedione,{{cite journal|last1=Finn|first1=Deborah A.|last2=Purdy|first2=Robert H.|title=Neuroactive Steroids in Anxiety and Stress|year=2007|doi=10.1002/9780470101001.hcn026|journal=Handbook of Contemporary Neuropharmacology|isbn=978-0470101001}} or 5α-pregnane-3,20-dione) is an endogenous progestogen and neurosteroid that is synthesized from progesterone.{{cite journal | vauthors = Mellon SH | title = Neurosteroid regulation of central nervous system development | journal = Pharmacol. Ther. | volume = 116 | issue = 1 | pages = 107–24 |date=October 2007 | pmid = 17651807 | pmc = 2386997 | doi = 10.1016/j.pharmthera.2007.04.011 }}{{cite journal | vauthors = Guidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E | title = The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders | journal = Brain Res. Brain Res. Rev. | volume = 37 | issue = 1–3 | pages = 110–5 |date=November 2001 | pmid = 11744079 | doi = 10.1016/s0165-0173(01)00129-1| s2cid = 22202599 }} 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.{{cite journal | vauthors = Rižner TL, Penning TM | title = Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism | journal = Steroids | volume = 79 | pages = 49–63 | date = January 2014 | pmid = 24189185 | pmc = 3870468 | doi = 10.1016/j.steroids.2013.10.012 }} AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one while AKR1C2 preferentially forms allopregnanolone. Similarly AKR1C1 reduces and consequently inactivates allopregnanolone into 5α-pregnane-3α,20α-diol. In contrast to the other AKRs, AKR1C3 has low catalytic efficiency for reduction of 5α-DHP. These AKRs are highly expressed in the human liver and mammary gland but have relatively modest expression in the human brain and uterus.{{cite journal | vauthors = Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K | title = 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 | journal = Biochem. J. | volume = 351 | issue = Pt 1 | pages = 67–77 | date = October 2000 | pmid = 10998348 | pmc = 1221336 | doi = 10.1042/bj3510067 }}

5α-DHP is an agonist of the progesterone receptor and a positive allosteric modulator of the GABA_A 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)).{{cite journal | vauthors = Rupprecht R, Reul JM, Trapp T | title = Progesterone receptor-mediated effects of neuroactive steroids | journal = Neuron | volume = 11 | issue = 3 | pages = 523–30 |date=September 1993 | pmid = 8398145 | doi = 10.1016/0896-6273(93)90156-l| s2cid = 11205767 |display-authors=etal}}{{cite journal|last1=Ocvirk|first1=Rok|last2=Pearson Murphy|first2=Beverley E.|last3=Franklin|first3=Keith B.J.|last4=Abbott|first4=Frances V.|title=Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test|journal=Pain|volume=138|issue=2|year=2008|pages=402–409|issn=0304-3959|doi=10.1016/j.pain.2008.01.019|pmid=18343034|s2cid=32370572}} It has also been found to act as a negative allosteric modulator of the GABA_A-rho receptor.{{cite journal | vauthors = Johnston GA | title = Medicinal chemistry and molecular pharmacology of GABA(C) receptors | journal = Curr Top Med Chem | volume = 2 | issue = 8 | pages = 903–13 | year = 2002 | pmid = 12171579 | doi = 10.2174/1568026023393453 | url = http://sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/350.pdf | archive-url = https://web.archive.org/web/20101226170919/http://sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/350.pdf | url-status = dead | archive-date = December 26, 2010 }} The steroid has been found to possess 82% of the affinity of progesterone for the progesterone receptor in rhesus monkey uterus.{{cite journal | vauthors = Illingworth DV, Elsner C, De Groot K, Flickinger GL, Mikhail G | title = A specific progesterone receptor of myometrial cytosol from the rhesus monkey | journal = J. Steroid Biochem. | volume = 8 | issue = 2 | pages = 157–60 | date = February 1977 | pmid = 405534 | doi = 10.1016/0022-4731(77)90040-1}} 5α-Dihydroprogesterone has been said to possess about 33% of the relative progestogenic potency of progesterone.{{cite book|author1=Rogerio A. Lobo|author2=Jennifer Kelsey|author3=Robert Marcus|title=Menopause: Biology and Pathobiology|url=https://books.google.com/books?id=i9HXKhjvNVAC&pg=PA433|date=22 May 2000|publisher=Academic Press|isbn=978-0-08-053620-0|pages=433–}} 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.{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = J. Clin. Invest. | volume = 102 | issue = 5 | pages = 1016–23 | year = 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}

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.{{cite journal | vauthors = Beyer C, González-Flores O, Ramírez-Orduña JM, González-Mariscal G | title = Indomethacin inhibits lordosis induced by ring A-reduced progestins: possible role of 3alpha-oxoreduction in progestin-facilitated lordosis | journal = Horm Behav | volume = 35 | issue = 1 | pages = 1–8 | date = February 1999 | pmid = 10049597 | doi = 10.1006/hbeh.1998.1457 | s2cid = 11520064 }}{{cite journal | vauthors = Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G | title = Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor | journal = Physiol. Behav. | volume = 58 | issue = 5 | pages = 985–93 | date = November 1995 | pmid = 8577898 | doi = 10.1016/0031-9384(95)00141-5 | s2cid = 25967801 }} 5α-DHP, via the progesterone receptor, and allopregnanolone, via the GABA_A receptor, act together to induce lordosis in animals. A study found that 41% of allopregnanolone that was administered via injection was transformed into 5α-DHP in the rat brain.

Levels of 5α-DHP have been quantified.{{cite journal | vauthors = Trabert B, Falk RT, Stanczyk FZ, McGlynn KA, Brinton LA, Xu X | title = Reproducibility of an assay to measure serum progesterone metabolites that may be related to breast cancer risk using liquid chromatography-tandem mass spectrometry | journal = Horm Mol Biol Clin Investig | volume = 23 | issue = 3 | pages = 79–84 | date = September 2015 | pmid = 26353176 | pmc = 4966666 | doi = 10.1515/hmbci-2015-0026 }}