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Isopregnanolone
Names
IUPAC name
3β-Hydroxy-5α-pregnan-20-one
Systematic IUPAC name
1-[(1S ,3aS ,3bR ,5aS ,7S ,9aS ,9bS ,11aS )-7-Hydroxy-9a,11a-dimethylhexadecahydro-1H -cyclopenta[a ]phenanthren-1-yl]ethan-1-one
Other names
Isoallopregnanolone; Epiallopregnanolone; Sepranolone; 3β,5α-Tetrahydroprogesterone; 3β,5α-THP
Identifiers
ChemSpider
ECHA InfoCard
100.007.478
UNII
InChI=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
Key: AURFZBICLPNKBZ-FZCSVUEKSA-N
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
Key: AURFZBICLPNKBZ-FZCSVUEKBS
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
Properties
C21 H34 O2
Molar mass
318.49 g/mol
Except where otherwise noted, data are given for materials in their
standard state (at 25 °C [77 °F], 100 kPa).
Chemical compound
Isopregnanolone , also known as isoallopregnanolone and epiallopregnanolone , as well as sepranolone (
INN Tooltip 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 .
[1]
[2] It has been reported to act as a
subunit -selective
negative allosteric modulator of the
GABAA receptor ,
[2] and
antagonizes in animals and humans some but not all of the GABAA receptor-mediated effects of allopregnanolone, such as
anesthesia ,
[3]
sedation ,
[4] and reduced
saccadic eye movements ,
[4] but not
learning impairment .
[2] 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 .
[1]
[5]
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)
[6] and can be reversibly metabolized into allopregnanolone by the enzyme
3α-hydroxysteroid dehydrogenase .
[1]
[2] Levels of isopregnanolone, progesterone, and allopregnanolone are highly correlated across the
menstrual cycle and throughout
pregnancy .
[1] The concentrations of isopregnanolone are significantly less than those of progesterone and allopregnanolone; about half of those of allopregnanolone, to be precise.
[6] Isopregnanolone has a relatively long serum
elimination half-life of 14 hours in humans.
[1]
Isopregnanolone (developmental code name UC-1010 ) is under development for the treatment of
premenstrual dysphoric disorder .
[7]
[8] As of 2017, it is in
phase II
clinical trials for this indication.
[7]
[8]
Chemistry
See also
References
^
a
b
c
d
e Hedström H, Bixo M, Nyberg S, Spigset O, Zingmark E, Bäckström T (2009).
"Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women" . Psychopharmacology . 203 (1): 85–98.
doi :
10.1007/s00213-008-1372-8 .
PMID
18949461 .
S2CID
720976 .
^
a
b
c
d 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
^ Bäckström T, Wahlström G, Wahlström K, Zhu D, Wang MD (2005). "Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats". Eur. J. Pharmacol . 512 (1): 15–21.
doi :
10.1016/j.ejphar.2005.01.049 .
PMID
15814085 .
^
a
b Bengtsson SK, Nyberg S, Hedström H, Zingmark E, Jonsson B, Bäckström T, Bixo M (2015). "Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans". Psychoneuroendocrinology . 52 : 22–31.
doi :
10.1016/j.psyneuen.2014.10.025 .
PMID
25459890 .
S2CID
25703203 .
^ Lundgren, Per; Strömberg, Jessica; Bäckström, Torbjörn; Wang, Mingde (2003). "Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3β-hydroxy-5α-pregnan-20-one (isoallopregnanolone)". Brain Research . 982 (1): 45–53.
doi :
10.1016/S0006-8993(03)02939-1 .
ISSN
0006-8993 .
PMID
12915239 .
S2CID
54297803 .
^
a
b Abraham Weizman (1 February 2008).
Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment . Springer Science & Business Media. pp. 8–9.
ISBN
978-1-4020-6854-6 .
^
a
b
"Sepranolone - Asarina Pharma - AdisInsight" .
^
a
b Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, Timby E, Wulff M, Ehrenborg A, Bäckström T (2017).
"Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial" . Psychoneuroendocrinology . 80 : 46–55.
doi :
10.1016/j.psyneuen.2017.02.031 .
PMID
28319848 .
External links
Ionotropic
GABAA Tooltip γ-Aminobutyric acid A receptor
Positive modulators (abridged; see
here for a full list):
α-EMTBL
Alcohols (e.g.,
drinking alcohol ,
2M2B )
Anabolic steroids
Avermectins (e.g.,
ivermectin )
Barbiturates (e.g.,
phenobarbital )
Benzodiazepines (e.g.,
diazepam )
Bromide compounds (e.g.,
potassium bromide )
Carbamates (e.g.,
meprobamate )
Carbamazepine
Chloralose
Chlormezanone
Clomethiazole
Dihydroergolines (e.g.,
ergoloid (dihydroergotoxine) )
Etazepine
Etifoxine
Fenamates (e.g.,
mefenamic acid )
Flavonoids (e.g.,
apigenin ,
hispidulin )
Fluoxetine
Flupirtine
Imidazoles (e.g.,
etomidate )
Kava constituents (e.g.,
kavain )
Lanthanum
Loreclezole
Monastrol
Neuroactive steroids (e.g.,
allopregnanolone ,
cholesterol ,
THDOC )
Niacin
Niacinamide
Nonbenzodiazepines (e.g.,
β-carbolines (e.g.,
abecarnil ),
cyclopyrrolones (e.g.,
zopiclone ),
imidazopyridines (e.g.,
zolpidem ),
pyrazolopyrimidines (e.g.,
zaleplon ))
Norfluoxetine
Petrichloral
Phenols (e.g.,
propofol )
Phenytoin
Piperidinediones (e.g.,
glutethimide )
Propanidid
Pyrazolopyridines (e.g.,
etazolate )
Quinazolinones (e.g.,
methaqualone )
Retigabine (ezogabine)
ROD-188
Skullcap constituents (e.g.,
baicalin )
Stiripentol
Sulfonylalkanes (e.g.,
sulfonmethane (sulfonal) )
Topiramate
Valerian constituents (e.g.,
valerenic acid )
Volatiles /
gases (e.g.,
chloral hydrate ,
chloroform ,
diethyl ether ,
paraldehyde ,
sevoflurane )
Negative modulators:
1,3M1B
3M2B
11-Ketoprogesterone
17-Phenylandrostenol
α3IA
α5IA (LS-193,268)
β-CCB
β-CCE
β-CCM
β-CCP
β-EMGBL
Anabolic steroids
Amiloride
Anisatin
β-Lactams (e.g.,
penicillins ,
cephalosporins ,
carbapenems )
Basmisanil
Bemegride
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IPTBO )
BIDN
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Cyclothiazide
DHEA
DHEA-S
Dieldrin
(+)-DMBB
DMCM
DMPC
EBOB
Etbicyphat
FG-7142 (ZK-31906)
Fiproles (e.g.,
fipronil )
Flavonoids (e.g.,
amentoflavone ,
oroxylin A )
Flumazenil
Fluoroquinolones (e.g.,
ciprofloxacin )
Flurothyl
Furosemide
Golexanolone
Iomazenil (123 I)
IPTBO
Isopregnanolone (sepranolone)
L-655,708
Laudanosine
Lindane
MaxiPost
Morphine
Morphine-3-glucuronide
MRK-016
Naloxone
Naltrexone
Nicardipine
Nonsteroidal antiandrogens (e.g.,
apalutamide ,
bicalutamide ,
enzalutamide ,
flutamide ,
nilutamide )
Oenanthotoxin
Pentylenetetrazol (pentetrazol)
Phenylsilatrane
Picrotoxin (i.e.,
picrotin ,
picrotoxinin and
dihydropicrotoxinin )
Pregnenolone sulfate
Propybicyphat
PWZ-029
Radequinil
Ro 15-4513
Ro 19-4603
RO4882224
RO4938581
Sarmazenil
SCS
Suritozole
TB-21007
TBOB
TBPS
TCS-1105
Terbequinil
TETS
Thujone
U-93631
Zinc
ZK-93426
GABAA -ρ Tooltip γ-Aminobutyric acid A-rho receptor
Metabotropic
GABAB Tooltip γ-Aminobutyric acid B receptor