Pregnanolone

Last updated
Pregnanolone
Eltanolone.svg
Names
IUPAC name
3α-Hydroxy-5β-pregnan-20-one
Systematic IUPAC name
1-[(1S,3aS,3bR,5aR,7R,9aS,9bS,11aS)-7-Hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]ethan-1-one
Other names
Eltanolone; 5β-Pregnan-3α-ol-20-one; 3α,5β-Tetrahydroprogesterone; 3α,5β-THP; 3α-Hydroxy-5β-tetrahydroprogesterone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.162.192 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
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-/m1/s1
    Key: AURFZBICLPNKBZ-YZRLXODZSA-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-/m1/s1
    Key: AURFZBICLPNKBZ-YZRLXODZBF
  • 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
C21H34O2
Molar mass 318.501 g·mol−1
Pharmacology
Intravenous injection [1]
Pharmacokinetics:
0.9–3.5 hours [1] [2] [3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. [4] It is closely related to allopregnanolone, which has similar properties. [4]

Contents

Biological activity

Pregnanolone is a positive allosteric modulator of the GABAA receptor, [4] as well as a negative allosteric modulator of the glycine receptor. [5]

Biological function

Pregnanolone has sedative, anxiolytic, anesthetic, and anticonvulsant effects. [4] [5] [1] During pregnancy, pregnanolone and allopregnanolone are involved in sedation and anesthesia of the fetus. [6] [7]

Biochemistry

Pregnanolone is synthesized from progesterone via the enzymes 5β-reductase and 3α-hydroxysteroid dehydrogenase, with 5β-dihydroprogesterone occurring as a metabolic intermediate. The elimination half-life of pregnanolone is between 0.9 and 3.5 hours. [1] [2] [3]

Chemistry

Pregnanolone, also known as 3α,5β-tetrahydroprogesterone (3α,5β-THP) or as 5β-pregnan-3α-ol-20-one, is a naturally occurring pregnane steroid and a derivative of progesterone. Related compounds include allopregnanolone (3α,5α-THP; brexanolone), epipregnanolone (3β,5β-THP), hydroxydione, isopregnanolone (3β,5α-THP), and renanolone.

History

Pregnanolone was first isolated from the urine of pregnant women in 1937. [1] Its anesthetic properties were first demonstrated in animals in 1957. [1]

Research

Pregnanolone was investigated for clinical use as a general anesthetic under the name eltanolone (INN), but produced unwanted side effects such as convulsions on occasion, and for this reason, was never marketed. [5] [8] [1]

Related Research Articles

<span class="mw-page-title-main">Progesterone</span> Sex hormone

Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.

<span class="mw-page-title-main">Androsterone</span> Endogenous steroid hormone

Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone. Androsterone is a metabolite of testosterone and dihydrotestosterone (DHT). In addition, it can be converted back into DHT via 3α-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase, bypassing conventional intermediates such as androstanedione and testosterone, and as such, can be considered to be a metabolic intermediate in its own right.

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

Alfaxolone/alfadolone (brand names Althesin, Saffan is a short acting intravenous anaesthetic agent. It was withdrawn from the market due to severe drug reactions. It is composed of a 3:1 mixture of alfaxalone and alfadolone, two neurosteroids.

<span class="mw-page-title-main">Etiocholanolone</span> Chemical compound

Etiocholanolone, also known as 5β-androsterone, as well as 3α-hydroxy-5β-androstan-17-one or etiocholan-3α-ol-17-one, is an etiocholane (5β-androstane) steroid as well as an endogenous 17-ketosteroid that is produced from the metabolism of testosterone. It causes fever, immunostimulation, and leukocytosis, and is used to evaluate adrenal cortex function, bone marrow performance, and in neoplastic disease to stimulate the immune system. Etiocholanolone is also known to be an inhibitory androstane neurosteroid, acting as a positive allosteric modulator of the GABAA receptor, and possesses anticonvulsant effects. The unnatural enantiomer of etiocholanolone is more potent as a positive allosteric modulator of GABAA receptors and as an anticonvulsant than the natural form.

<span class="mw-page-title-main">Allopregnanolone</span> Endogenous inhibitory neurosteroid

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.

<span class="mw-page-title-main">Alfaxalone</span> Chemical compound

Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable anesthetic. Though it is more expensive than other induction agents, it often preferred due to the lack of depressive effects on the cardiovascular system. The most common side effect seen in current veterinary practice is respiratory depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; when premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up.

<span class="mw-page-title-main">3α-Androstanediol</span> Chemical compound

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).

<span class="mw-page-title-main">5α-Dihydroprogesterone</span> Chemical compound

5α-Dihydroprogesterone is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone.

GABA<sub>A</sub> receptor positive allosteric modulator

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

<span class="mw-page-title-main">Isopregnanolone</span> Chemical compound

Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone (INN), 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. 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, sedation, 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.

<span class="mw-page-title-main">Epipregnanolone</span> Chemical compound

Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiators like allopregnanolone. Epipregnanolone is biosynthesized from progesterone by the actions of 5β-reductase and 3β-hydroxysteroid dehydrogenase, with 5β-dihydroprogesterone as the intermediate in this two-step transformation.

<span class="mw-page-title-main">5β-Dihydroprogesterone</span> Chemical compound

5β-Dihydroprogesterone is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone. It is synthesized from progesterone by the enzyme 5β-reductase.

<span class="mw-page-title-main">3α-Dihydroprogesterone</span> Chemical compound

3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid. It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone. 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action. In accordance, it has anxiolytic effects in animals. 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties. Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride. No data were available on the progestogenic activity of 3α-DHP as of 1977. Levels of 5α-DHP have been quantified.

<span class="mw-page-title-main">3β-Dihydroprogesterone</span> Chemical compound

3β-Dihydroprogesterone (3β-DHP), also known as 3β-hydroxyprogesterone, or pregn-4-en-3β-ol-20-one, is an endogenous steroid. It is biosynthesized by 3β-hydroxysteroid dehydrogenase from progesterone. Unlike 3α-dihydroprogesterone (3α-DHP), 3β-DHP does not act as a positive allosteric modulator of the GABAA receptor, which is in accordance with the fact that other 3β-hydroxylated progesterone metabolites such as isopregnanolone and epipregnanolone similarly do not act as potentiators of this receptor and instead inhibit it as well as reverse the effects of potentiators like allopregnanolone. 3β-DHP has been reported to possess about the same potency as progesterone in a bioassay of progestogenic activity, whereas 3α-DHP was not assessed.

<span class="mw-page-title-main">Zuranolone</span> Chemical compound

Zuranolone is an investigational medication which is under development by SAGE Therapeutics for the treatment of depressive disorders and a variety of other indications. It is a synthetic, orally active, inhibitory pregnane neurosteroid, and acts as a positive allosteric modulator of the GABAA receptor. The drug was developed as an improvement on the intravenously-administered neurosteroid brexanolone (allopregnanolone), with high oral bioavailability and a biological half-life suitable for once-daily administration. Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone. As of December 2022, zuranolone is in preregistration for major depressive disorder and postpartum depression, phase III clinical trials for insomnia, and phase II clinical studies for bipolar depression, essential tremor, and Parkinson's disease. Zuranolone has also been investigated for treatment of dyskinesias and seizures, but no further development has been reported for these indications.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Pregnenolone (medication)</span> Medication and supplement

Pregnenolone, sold under the brand name Enelone among others, is a medication and supplement as well as a naturally occurring and endogenous steroid. It is described as a neurosteroid and anti-inflammatory drug and was used in the treatment of rheumatoid arthritis and soft-tissue rheumatism in the 1950s but is no longer used today. Pregnenolone can be taken by mouth, as a topical medication, or by injection into muscle.

<span class="mw-page-title-main">Pharmacokinetics of progesterone</span>

The pharmacokinetics of progesterone, concerns the pharmacodynamics, pharmacokinetics, and various routes of administration of progesterone.

References

  1. 1 2 3 4 5 6 7 Carl P, Høgskilde S, Lang-Jensen T, et al. (October 1994). "Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans". Acta Anaesthesiol Scand. 38 (7): 734–41. doi:10.1111/j.1399-6576.1994.tb03987.x. PMID   7839787. S2CID   22005284.
  2. 1 2 Gray HS, Holt BL, Whitaker DK, Eadsforth P (March 1992). "Preliminary study of a pregnanolone emulsion (Kabi 2213) for i.v. induction of general anaesthesia". Br J Anaesth. 68 (3): 272–6. doi: 10.1093/bja/68.3.272 . PMID   1547051. S2CID   19193898.
  3. 1 2 Carl P, Høgskilde S, Nielsen JW, Sørensen MB, Lindholm M, Karlen B, Bäckstrøm T (March 1990). "Pregnanolone emulsion. A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent". Anaesthesia. 45 (3): 189–97. doi: 10.1111/j.1365-2044.1990.tb14683.x . PMID   2334030. S2CID   28358731.
  4. 1 2 3 4 Reddy DS (2003). "Pharmacology of endogenous neuroactive steroids". Crit Rev Neurobiol. 15 (3–4): 197–234. doi:10.1615/critrevneurobiol.v15.i34.20. PMID   15248811.
  5. 1 2 3 Jürgen Schüttler; Helmut Schwilden (8 January 2008). Modern Anesthetics. Springer Science & Business Media. pp. 278–. ISBN   978-3-540-74806-9.
  6. ↑ Mellor DJ, Diesch TJ, Gunn AJ, Bennet L (2005). "The importance of 'awareness' for understanding fetal pain". Brain Res. Brain Res. Rev. 49 (3): 455–71. doi:10.1016/j.brainresrev.2005.01.006. PMID   16269314. S2CID   9833426.
  7. ↑ Lagercrantz H, Changeux JP (2009). "The emergence of human consciousness: from fetal to neonatal life". Pediatr. Res. 65 (3): 255–60. doi: 10.1203/PDR.0b013e3181973b0d . PMID   19092726. S2CID   39391626. [...] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36).
  8. ↑ Norman Calvey; Norton Williams (21 January 2009). Principles and Practice of Pharmacology for Anaesthetists. John Wiley & Sons. pp. 110–. ISBN   978-1-4051-9484-6.


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