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Allopregnanolone

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Allopregnanolone, also known as Sepranolone and Isopregnanolone, is a GABA receptor modulating steroid antagonist and 11-betahydroxysteroid dehydrogenase type 1 (11β-HSD1)…

Product Description

Basic Characteristics

Product Name Allopregnanolone
CAS Number 516-55-2
Molecular Formula C21H34O2
Formula Weight 318.5
Synonyms NSC-97078; U-0949; UC-1010; NSC97078; U0949; UC1010; NSC 97078; U 0949; UC 1010; Isopregnanolone; Allopregnanolon; Sepranolone; 516-55-2; 5alpha-Pregnan-3beta-ol-20-one
Appearance White powder
Storage and Handling Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).

 

Allopregnanolone Description

Allopregnanolone, also known as Sepranolone and Isopregnanolone, is a GABA receptor modulating steroid antagonist and 11-betahydroxysteroid dehydrogenase type 1 (11β-HSD1). Sepranolone is a powerful neurological compound, produced naturally in the body, that modulates the effects of Allopregnanolone (ALLO). ALLO is a potent neurosteroid implicated in stress- and compulsion-related conditions ranging from Tourette to OCD, PTSD, compulsive gambling, addiction, PMDD, Menstrual Migraine.

 

Allopregnanolone Mechanism of Action

Molecular interactions

Allopregnanolone is an endogenous inhibitory pregnane neurosteroid. It is made from progesterone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity. Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation. Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors, and also appears to act as a negative allosteric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.

 

Antidepressant effects

The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, despite clinicians prescribing Alprazolam for depression in the past. Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines. As examples, GABAA receptor-potentiating neurosteroids may preferentially target δ subunit-containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors. It is also possible that neurosteroids like allopregnanolone may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.

 

Allopregnanolone Application

Allopregnanolone is a naturally produced steroid that acts on the brain. As a medication, it is sold under the brand name Zulresso and used to treat postpartum depression. It is used by injection into a vein over a 60-hour period under medical supervision.

Side effects of Allopregnanolone may include sedation, sleepiness, dry mouth, hot flashes, and loss of consciousness. It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Allopregnanolone was approved for medical use in the United States in 2019. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.

 

Reference

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[2] Horishita T, Yanagihara N, Ueno S, Sudo Y, Uezono Y, Okura D, Minami T, Kawasaki T, Sata T. Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the α subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes. Anesthesiology. 2014 Sep;121(3):620-31. doi: 10.1097/ALN.0000000000000296. PubMed PMID: 24809977.

[3] Zorumski CF, Paul SM, Covey DF, Mennerick S (November 2019). “Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond”. Neurobiology of Stress. 11: 100196. doi:10.1016/j.ynstr.2019.100196. PMC 6804800. PMID 31649968.

[4] Warner, M. D.; Peabody, C. A.; Whiteford, H. A.; Hollister, L. E. (April 1988). “Alprazolam as an antidepressant”. The Journal of Clinical Psychiatry. 49 (4): 148–150. ISSN 0160-6689. PMID 3281931.

[5] Srisurapanont, M.; Boonyanaruthee, V. (1997). Alprazolam and standard antidepressants in the treatment of depression: a meta-analysis of the antidepressant effect. Centre for Reviews and Dissemination (UK). PMID 9175386.

[6] Reddy DS (2010). Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog. Brain Res. Progress in Brain Research. 186. pp. 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. PMC 3139029. PMID 21094889.

[7] Bullock AE, Clark AL, Grady SR, Robinson SF, Slobe BS, Marks MJ, et al. (June 1997). “Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes”. Journal of Neurochemistry. 68 (6): 2412–23. doi:10.1046/j.1471-4159.1997.68062412.x. PMID 9166735.

[8] Slavíková B, Bujons J, Matyáš L, Vidal M, Babot Z, Krištofíková Z, Suñol C, Kasal A. Allopregnanolone and pregnanolone analogues modified in the C ring: synthesis and activity. J Med Chem. 2013 Mar 28;56(6):2323-36. doi: 10.1021/jm3016365. PubMed PMID: 23421641.