Isopregnanolone

{{Chembox | ImageFile = Isopregnanolone.svg | ImageClass = skin-invert-image | ImageSize = 225px | ImageAlt = | IUPACName = 3β-Hydroxy-5α-pregnan-20-one | SystematicName = 1-[(1''S'',3a''S'',3b''R'',5a''S'',7''S'',9a''S'',9b''S'',11a''S'')-7-Hydroxy-9a,11a-dimethylhexadecahydro-1''H''-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 = | Density = | MeltingPt = | BoilingPt = | Solubility = }} | Section3 = {{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}

'''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.<ref name="pmid18949461">{{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://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-49365 }}</ref><ref name="Ofverman2009">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</ref> It has been reported to act as a subunit-selective negative allosteric modulator of the GABAA receptor,<ref name="Ofverman2009" /> and antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as anesthesia,<ref name="pmid15814085">{{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 }}</ref> sedation,<ref name="pmid25459890">{{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 }}</ref> and reduced saccadic eye movements,<ref name="pmid25459890" /> but not learning impairment.<ref name="Ofverman2009" /> 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.<ref name="pmid18949461" /><ref name="LundgrenStrömberg2003">{{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}}</ref>

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)<ref name="Weizman2008">{{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}}</ref> and can be reversibly metabolized into allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase.<ref name="pmid18949461" /><ref name="Ofverman2009" /> Levels of isopregnanolone, progesterone, and allopregnanolone are highly correlated across the menstrual cycle and throughout pregnancy.<ref name="pmid18949461" /> The concentrations of isopregnanolone are significantly less than those of progesterone and allopregnanolone; about half of those of allopregnanolone, to be precise.<ref name="Weizman2008" /> Isopregnanolone has a relatively long serum elimination half-life of 14 hours in humans.<ref name="pmid18949461" />

Isopregnanolone (developmental code name '''UC-1010''') was under development for the treatment of premenstrual dysphoric disorder.<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800036513|title = Sepranolone - Asarina Pharma - AdisInsight|access-date=2026-04-29}}</ref><ref name="pmid28319848">{{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 = http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-136320 }}</ref>, however development was suspended indefinitely after phase IIb clinical trial results, while positive, showed an elevated placebo response rate.<ref name="pmid28319848" /><ref>{{cite-web|title=Phase IIb post-hoc analysis|author=Asarina Pharma|url=https://asarinapharma.com/pmdd/phase-iib-post-hoc-analysis/|access-date=2026-04-29}}</ref> Development of isopregnanolone as a treatment for Tourette's syndrome has continued, with phase II trials planned to take place in 2026.<ref name="AdisInsight" />

==References== {{Reflist|2}}

==External links== * [http://adisinsight.springer.com/drugs/800036513 Sepranolone - AdisInsight] * [http://www.asarinapharma.com/sepranolone Sepranolone - Asarina Pharma]

Category:GABAA receptor negative allosteric modulators Category:Neurosteroids Category:Pregnanes