567-02-2

Usage

Uses

Used in Pharmaceutical Industry:
21-Hydroxyallopregnanolone is used as a γ-aminobutyric acid type A receptor (γ-GABAA) agonist for its potential therapeutic effects on various neurological conditions. It has been studied in voltage-clamp measurements in Xenopus oocytes to test its impact on spike-wave discharges (SWD) in finasteride-treated rats.
Used in Electrophysiological Studies:
In the field of neuroscience, 21-Hydroxyallopregnanolone is utilized in electrophysiological studies with dentate granule cells (DGCs) post-controlled cortical impact (CCI)-induced brain injury. This application aims to understand its potential role in neuroprotection and recovery following brain injuries.
Used in Neurological Research:
21-Hydroxyallopregnanolone is also used in neurological research to explore its effects on the central nervous system, particularly in modulating the GABAergic system, which is crucial for maintaining neuronal excitability and preventing hyperexcitability-related disorders.

Biochem/physiol Actions

3α,21-Dihydroxy-5α-pregnan-20-one (THDOC) is a positive allosteric modulator of the γ-aminobutyric acid A receptor (GABAA). By modulating GABAA receptor, THDOC allows sustained hyperpolarization and an increase in chloride influx and membrane conductance in neurons. THDOC, thus modulates neuronal excitability. It possesses anxiolytic, anticonvulsant and sedative properties. The levels of THDOC show variation in different physiological states. A low THDOC level in the mensural phase is speculated to play a role in the pathogenesis of catamenial epilepsy (CE) in women. However, elevated levels are reported in depression. THDOC may have an indirect role in the hypothalamic-pituitary–adrenal (HPA) axis activation during acute stress.

InChI:InChI=1/C21H34O3/c1-20-9-7-14(23)11-13(20)3-4-15-16-5-6-18(19(24)12-22)21(16,2)10-8-17(15)20/h13-18,22-23H,3-12H2,1-2H3

Upstream product

• 911451-83-7 21,21-bis-benzyloxy-3β-hydroxy-pregn-5-en-20-one 
• 56-47-3 deoxycorticosterone acetate 
• 64-17-5 ethanol 
• 96611-83-5 3β-hydroxy-20-oxo-5α-pregnan-21-yl acetate 
• 225518-93-4 2-(tert-Butyl-dimethyl-silanyloxy)-1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-(tert-butyl-dimethyl-silanyloxy)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-17-yl]-ethanone 
• 516-55-2 isopregnanolone 
• 96038-59-4 3α,21-diacetoxy-5α-pregnan-20-one 
• 225518-89-8 (3R,5S,8R,9S,10S,13S,14S,17S)-3-(tert-Butyl-dimethyl-silanyloxy)-17-[1-(tert-butyl-dimethyl-silanyloxy)-vinyl]-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthrene 
• 566-65-4 dihydroprogesterone 
• 516-54-1 tetrahydroprogesterone 
• 2402-24-6 (3β,5α)-21-(acetyloxy)-3-hydroxypregnan-20-one 
• 566-78-9 21-acetoxypregnenolone 
• 298-36-2 5α-pregnan-21-ol-3,20-dione 
• 51296-50-5 (3β,5α)-21-bromo-3-hydroxypregnan-20-one 

Relevant academic research and scientific papers

Suppressing aggressive behavior with analogs of allopregnanolone (epalon)

3α-Hydroxy-20-oxo-5α-pregnan-21-yl hemisuccinate (8) was produced by partial acylation of 3α,21-dihydroxy-5α-pregnan-20-one (14). 3α-Fluoro-5α-pregnan-20-one (9) was prepared by treatment of 3β-hydroxy-5α-pregnan-20-one (11) with DAST and by solvolysis of tosylate 12 with tetrabutylammonium fluoride. A behavioral test on mice was performed using 3α-hydroxy-5α-pregnan-20-one (1) and compounds 8 and 9. Compound 8 was found to be inactive, while the fluoro derivative 9 selectively reduced aggressive behavior in mice more than the corresponding 3α-hydroxy compound 1; locomotion and other behavioral features were not affected. Copyright

Synthesis, Metabolism, and Pharmacological Activity of 3α-Hydroxy Steroids Which Potentiate GABA-Receptor-Mediated Chloride Ion Uptake in Rat Cerebral Cortical Synaptoneurosomes

Certain 3α-hydroxy steroids have recently been shown to bind to the γ-aminobutyric acid (GABA) receptor gated chloride ion channel with high affinity and to potentiate the inhibitory effects of GABA when measured both in vitro and in vivo.In the present study, a series of natural and synthetic 3α-hydroxy steroids were tested for their ability to potentiate GABA-receptor-mediated chloride ion (Cl-) uptake into cerebral cortical synaptoneurosomes.The naturally occurring metabolites 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) and 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydroDOC) were found to be the most active in augmenting GABAA-receptor-mediated Cl- uptake.Pharmacological activity was reduced in the corresponding isomers with the 5β-pregnane configuration and by some, but not all, modifications of the side chain.The ability of these steroids to potentiate muscimol-stimulated Cl- uptake is lost by acetylation at C3, introduction of unsaturation at C9(11), inversion to the 3β-hydroxy isomer, or inversion of configuration at C17.A facile procedure is reported for synthesis of unlabeled and tritium-labeled allopregnolane and allotetrahydro DOC.The 9α,11α,12α-3H-labeled derivatives of allopregnanolone and allotetrahydro DOC were used to identify the distribution and metabolic products af these active steroids.Uptake of the more hydrophobic 3H>allopregnanolone into brain was significantly greater than that of 3H>allotetrahydroDOC.The principal 3H-labeled metabolites recovered from brain were the 3-ketone derivatives of allopregnanolone and allotetrahydroDOC, which are both inactive an GABA-receptor-mediated Cl- flux.Molecular modeling of active steroids based on quantitative structure-activity relationships provides evidence to support the stereospecificity of the binding interactions and suggests that there may be more than one type of steroid binding site associated with the GABAA-receptor-mediated chloride ionophore.

INHIBITORS OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE FOR TREATING CARDIOVASCULAR AND PULMONARY CONDITIONS

The present disclosure provides for methods of treating or preventing a cardiovascular disorder and/or a related pulmonary disorder in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of an inhibitor of Glucose-6-phosphate dehydrogenase (G6PD), or a pharmaceutically acceptable salt, non-salt amorphous form, solvate, poly-morph, tautomer or prodrug thereof.

Characterization of rabbit aldose reductase-like protein with 3β-hydroxysteroid dehydrogenase activity

In this study, we isolated the cDNA for a rabbit aldose reductase-like protein that shared an 86% sequence identity to human aldo-keto reductase (AKR)1 1B10 and has been assigned as AKR1B19 in the AKR superfamily. The purified recombinant AKR1B19 was similar to AKR1B10 and rabbit aldose reductase (AKR1B2) in the substrate specificity for various aldehydes and α-dicarbonyl compounds. In contrast to AKR1B10 and AKR1B2, AKR1B19 efficiently reduced 3-keto-5α/β-dihydro-C19/C21/C24-steroids into the corresponding 3β-hydroxysteroids, showing Km of 1.3-9.1 μM and kcat of 1.1-7.6 min-1. The stereospecific reduction was also observed in the metabolism of 5α- and 5β- dihydrotestosterones in AKR1B19-overexpressing cells. The mRNA for AKR1B19 was ubiquitously expressed in rabbit tissues, and the enzyme was co-purified with 3β-hydroxysteroid dehydrogenase activity from the lung. Thus, AKR1B19 may function as a 3-ketoreductase, as well as a defense system against cytotoxic carbonyl compounds in rabbit tissues. The molecular determinants for the unique 3-ketoreductase activity were investigated by replacement of Phe303 and Met304 in AKR1B19 with Gln and Ser, respectively, in AKR1B10. Single and double mutations (F303Q, M304S and F303Q/M304S) significantly impaired this activity, suggesting the two residues play critical roles in recognition of the steroidal substrate.

Novel steroid inhibitors of glucose 6-phosphate dehydrogenase

Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3β-alcohol can be replaced with 3β-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.

Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity

An Henbest reduction, followed by the preparation of a silyl enol ether and oxidation in situ with m-CPBA has led to the neurosteroids 3α-hydroxy- and 3α,21-dihydroxy-5α-pregnanolones. Using testosterone as starting material, a new short synthesis of an aromatase inhibitor, 4-OHA, has been achieved through hydroboration/oxidation followed by a Swern type oxidation and epimerization. Another aromatase inhibitor, androst-4-ene-3,6,17-trione, has been efficiently prepared using PCC on montmorillonite K10, under ultrasonic irradiation.

Biotransformation of corticosteroids by Penicillium decumbens ATCC 10436

The biotransformation of a series of corticosteroids by the fungus Penicillium decumbens ATCC 10436 has been investigated. Conversion to the corresponding 5α-dihydroxteroid was observed for all the Δ4-3-ketosteroids studied with the exception of deoxycorticosterone, which was converted to a Δ14-diene. Deoxycorticosterone acetate was, however, converted to a 5α- dihydro product concomitant with ester hydrolysis. Other substrates carrying a C-21 acetoxy group were also hydrolyzed to the alcohol. In two cases (resulting from deoxycorticosterone acetate and 11-deoxycortisone) the 5α- 3-keto-product was further reduced to the 3β-alcohol. No reduction of δ14-dienes was observed.

METHODS, COMPOSITIONS, AND COMPOUNDS FOR ALLOSTERIC MODULATION OF THE GABA RECEPTOR BY MEMBERS OF THE ANDROSTANE AND PREGNANE SERIES

Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, insomnia and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-aminobutyric acid receptor-chloride ionophore (GR) complex.