isopregnanolone
{{Chembox
| ImageFile = Isopregnanolone.svg
| ImageSize = 225px
| ImageAlt =
| IUPACName = 3β-Hydroxy-5α-pregnan-20-one
| SystematicName = 1-[(1S,3aS,3bR,5aS,7S,9aS,9bS,11aS)-7-Hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]ethan-1-one
| OtherNames = Isoallopregnanolone; Epiallopregnanolone; Sepranolone; 3β,5α-Tetrahydroprogesterone; 3β,5α-THP
| Section1 = {{Chembox Identifiers
| CASNo = 516-55-2
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3P8Z6V53MU
| PubChem = 92787
| ChemSpiderID = 83761
| SMILES = CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@@H](C4)O)C)C
| InChI = 1/C21H34O2/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/h14-19,23H,4-12H2,1-3H3/t14-,15-,16-,17+,18-,19-,20-,21+/m0/s1
| InChIKey = AURFZBICLPNKBZ-FZCSVUEKBS
| StdInChI = 1S/C21H34O2/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/h14-19,23H,4-12H2,1-3H3/t14-,15-,16-,17+,18-,19-,20-,21+/m0/s1
| StdInChIKey = AURFZBICLPNKBZ-FZCSVUEKSA-N
}}
| Section2 = {{Chembox Properties
| Formula = C21H34O2
| MolarMass = 318.49 g/mol
| Appearance =
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| Section3 = {{Chembox Hazards
| MainHazards =
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Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone ({{abbrlink|INN|International Nonproprietary Name}}), and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of allopregnanolone.{{cite journal | vauthors = Hedström H, Bixo M, Nyberg S, Spigset O, Zingmark E, Bäckström T | title = Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women | journal = Psychopharmacology | volume = 203 | issue = 1 | pages = 85–98 | year = 2009 | pmid = 18949461 | doi = 10.1007/s00213-008-1372-8 | s2cid = 720976 | url =http://umu.diva-portal.org/smash/get/diva2:455421/FULLTEXT02 }}Öfverman, C., Strömberg, J., Birzniece, V., Turkmen, S., Hill, M., Lundgren, P., ... & Johansson, I. M. (2009). The progesterone metabolite isoallopregnanolone is a subunit-selective antagonist of the GABA-A receptor. Chicago It has been reported to act as a subunit-selective negative allosteric modulator of the GABAA receptor, and antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as anesthesia,{{cite journal | vauthors = Bäckström T, Wahlström G, Wahlström K, Zhu D, Wang MD | title = Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats | journal = Eur. J. Pharmacol. | volume = 512 | issue = 1 | pages = 15–21 | year = 2005 | pmid = 15814085 | doi = 10.1016/j.ejphar.2005.01.049 }} sedation,{{cite journal | vauthors = Bengtsson SK, Nyberg S, Hedström H, Zingmark E, Jonsson B, Bäckström T, Bixo M | title = Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans | journal = Psychoneuroendocrinology | volume = 52 | pages = 22–31 | year = 2015 | pmid = 25459890 | doi = 10.1016/j.psyneuen.2014.10.025 | s2cid = 25703203 }} and reduced saccadic eye movements, but not learning impairment. Isopregnanolone has no hormonal effects and appears to have no effect on the GABAA receptor by itself; it selectively antagonizes allopregnanolone and does not affect the effects of other types of GABAA receptor positive allosteric modulators such as benzodiazepines or barbiturates.{{cite journal|last1=Lundgren|first1=Per|last2=Strömberg|first2=Jessica|last3=Bäckström|first3=Torbjörn|last4=Wang|first4=Mingde|title=Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3β-hydroxy-5α-pregnan-20-one (isoallopregnanolone)|journal=Brain Research|volume=982|issue=1|year=2003|pages=45–53|issn=0006-8993|doi=10.1016/S0006-8993(03)02939-1|pmid=12915239|s2cid=54297803}}
Isopregnanolone is synthesized from progesterone in the body by the actions of the enzymes 5α-reductase and 3β-hydroxysteroid dehydrogenase (with 5α-dihydroprogesterone as the intermediate in this two-step transformation){{cite book|author=Abraham Weizman|title=Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment|url=https://books.google.com/books?id=uABKkFdPjhkC&pg=PA8|date=1 February 2008|publisher=Springer Science & Business Media|isbn=978-1-4020-6854-6|pages=8–9}} and can be reversibly metabolized into allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase. Levels of isopregnanolone, progesterone, and allopregnanolone are highly correlated across the menstrual cycle and throughout pregnancy. The concentrations of isopregnanolone are significantly less than those of progesterone and allopregnanolone; about half of those of allopregnanolone, to be precise. Isopregnanolone has a relatively long serum elimination half-life of 14 hours in humans.
Isopregnanolone (developmental code name UC-1010) is under development for the treatment of premenstrual dysphoric disorder.{{Cite web|url=http://adisinsight.springer.com/drugs/800036513|title = Sepranolone - Asarina Pharma - AdisInsight}}{{cite journal | vauthors = Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, Timby E, Wulff M, Ehrenborg A, Bäckström T | title = Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial | journal = Psychoneuroendocrinology | volume = 80 | pages = 46–55 | year = 2017 | pmid = 28319848 | doi = 10.1016/j.psyneuen.2017.02.031 | doi-access = free | url = https://umu.diva-portal.org/smash/get/diva2:1115054/FULLTEXT01 }} As of 2017, it is in phase II clinical trials for this indication.
Chemistry
{{See also|List of neurosteroids}}
See also
References
{{Reflist|2}}
External links
- [http://adisinsight.springer.com/drugs/800036513 Sepranolone - AdisInsight]
- [http://www.asarinapharma.com/sepranolone Sepranolone - Asarina Pharma]
{{Endogenous steroids}}
{{GABA receptor modulators}}