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Chemical Compound Review:

Allopregnanolone 1- [(3R,5S,8S,9S,10S,13S,14S,17S) -3-hydroxy...

Synonyms: Allopregnalone, CHEMBL207538, SureCN588060, CHEBI:50169, P8887_SIGMA, ...

Reddy, D.S. et al., Strömstedt, M. et al., Belelli, D. et al., Frye, C.A. et al., Serra, M. et al., et al.

Pearson Murphy, Steinberg, Hu, Allison, Grobin, VanDoren, Porrino, Morrow, Smith, Wekstein, Markesbery, Frye, Paoletti, Romagnino, Contu, Orrù, Marotto, Zedda, Lello, Biggio, Concas, Melis, Serra, Mostallino, Talani, Pisu, Carta, Mura, Floris, Maciocco, Sanna, Biggio, Serra, Pisu, Floris, Floris, Cannas, Mossa, Trapani, Latrofa, Purdy, Biggio, Khisti, Chopde,

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Disease relevance of C13712

Data are reviewed that support the notion that: 1) effects of 3alpha-hydroxy-5alpha-pregnan-20-one in the midbrain ventral tegmental area facilitate lordosis and other reproductively-relevant behaviors [1].
Adenosinergic modulation of 3alpha-hydroxy-5alpha-pregnan-20-one induced catalepsy in mice [2].
Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors [3].
Ethanol-induced elevation of 3 alpha-hydroxy-5 alpha-pregnan-20-one does not modulate motor incoordination in rats [4].

Psychiatry related information on C13712

RESULTS: The notable finding was the significantly lower 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) level in demented subjects compared with controls (25% decrease; p=0.004); 3alpha,5alpha-THP was the only one of the steroids demonstrating an effect of dementia [5].
RATIONALE: Greater incidence of anxiety and depressive disorders of women compared to men may be due in part to progesterone (P) and its neuroactive metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), acting in limbic regions, such as the amygdala [6].
SCL-90 psychometric scale, circulating levels of progesterone (P4), 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone, AP), 3alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxy-corticosterone, THDOC), cortisol and DHEAS were assayed at each visit [7].

High impact information on C13712

By 7 wk postpartum, only 3 alpha,5 alpha-tetrahydroprogesterone and 3 beta,5 beta-tetrahydroprogesterone remained slightly elevated (P < or = 0.012 and 0.007, respectively) [8].
BACKGROUND: The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) has anxiolytic and anticonvulsant properties, potentiating GABA(A) receptor chloride channel function with 20-fold higher potency than benzodiazepines [9].
The velocity of the reaction was similar in incubations in which the pH was varied from 6.0-8.0, and NADH and NADPH were equally effective in supporting the 6alpha-hydroxylation of 5alpha-pregnan-3beta-ol-20-one and 5alpha-pregnan-3alpha-ol-20-one [10].
Progesterone, through conversion to its neurosteroid metabolite 3 alpha-OH DHP, potentiates GABA responses of cerebellar Purkinje cells [11].
The role of brain cytochrome P450 (P450) in regulating the levels of the potent anesthetic steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) has been investigated [12].

Chemical compound and disease context of C13712

Duration and intensity of lordosis is mediated by actions of the progesterone (P) metabolite, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) at GABA-sub(A) receptors in the midbrain ventral tegmental area [13].
Progesterone facilitates and 5alpha-dihydrotestosterone (DHT) inhibits female sexual behaviour in rodents; their metabolites, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) and 5alpha-androstane-3alpha-17beta-Diol (3alpha-Diol), may influence the onset and termination of lordosis [14].

Biological context of C13712

To test the hypothesis that the hydroxylation of 3 beta-OH-DHP represents a pathway for regulation of the level of 3 alpha-OH-DHP in the brain, the effect of inhibition of the hydroxylation of 3 beta-OH-DHP on the duration of 3 alpha-OH-DHP-induced anesthesia was examined [12].
A series of analogues of the neuroactive steroids 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one were studied to elucidate the mode of binding of 5 alpha-and 5 beta-reduced steroids to steroid binding sites on GABAA receptors [15].
Conversely, Ro 5-4864 opposed the action of 3 alpha-OH-DHP by increasing the IC50 for 3 alpha-OH-DHP inhibition of [35S]TBPS binding [16].
Recent in vitro work in our laboratory suggests that functional sensitivity of the gamma-aminobutyric acidA receptor complex to the neuroactive progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) changes during the estrus cycle [17].
Discriminative stimulus effects of ethanol and 3 alpha-hydroxy-5 alpha-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis) [18].

Anatomical context of C13712

As reported in neurons and in other expression systems, GABAA responses expressed in oocytes by cerebral cortex RNA were strongly and stereospecifically potentiated by 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP) and 5 alpha-pregnan-3 alpha,21-diol-20-one (THDOC) [19].
It also catalyzes the formation of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in the central nervous system, and its allosteric modulation by fluoxetine has been linked to the use of this drug for premenstrual dsyphoria [20].
3alpha-hydroxy-5alpha-pregnan-20-one in the midbrain ventral tegmental area mediates social, sexual, and affective behaviors [1].
The influence of the subunit composition of human GABA(A) receptors upon the GABA-modulatory properties of 5alpha-pregnan-3alpha-ol-20-one (5alpha,3alpha) has been examined using the Xenopus laevis oocyte expression system and the two electrode voltage-clamp technique [21].
Our aim was to examine the effect of the potent neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P) on [3H]-GABA binding to its receptor sites in the chick optic lobe [22].

Associations of C13712 with other chemical compounds

Previously we have demonstrated that social isolation of rats reduces both the cerebrocortical and plasma concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG), and potentiates the positive effects of acute ethanol administration on the concentrations of this neurosteroid [23].
The plasma concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG), 3alpha,21-dihydroxy-5alpha-pregnan-20-one, progesterone, and cortisol were determined in 17 outpatients with BD, 14 outpatients with MDD, and 16 healthy control subjects [24].
The metabolites, 5alpha-pregnane-3,20-dione, 3alpha-hydroxy-5alpha-pregnan-20-one, and 3beta-hydroxy-5alpha-pregnan-20-one, were identified by isolation and purification by thin-layer chromatography and reverse isotope dilution, followed by recrystallization of the free compound and a derivative [25].
These findings provide the initial evidence that the GBRC-linked Ro 5-4864 binding site is allosterically coupled to the putative progesterone metabolite recognition site and confirm the GABA-mimetic properties of 3 alpha-OH-DHP and pregnanediol [16].
Social isolation of rats for 30 days immediately after weaning reduces the cerebrocortical and plasma concentrations of progesterone, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG), and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) [26].

Gene context of C13712

Ventral tegmental area (VTA) infusions of the MBR agonist, FGIN 1-27, increase midbrain levels of the progesterone metabolite 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) and lordosis of rats and hamsters [27].
Cortical 3 alpha-hydroxy-5 alpha-pregnan-20-one levels after acute administration of Delta 9-tetrahydrocannabinol, cocaine and morphine [28].
The effects of enantiomers of the neurosteroid analogues, 3alpha-hydroxy-5alpha-pregnan-20-one (DHP) and 3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile (ACN), and the benz[e]indene, BI-1, on synaptic currents were examined in microcultures of rat hippocampal neurons [29].
The present study demonstrated the antidepressant-like effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha, 5alpha THP) in mouse forced swim test of depression and its modulation by different serotonergic agents [30].
Both neurosteroids are equally active on various types of recombinant GABAA receptors, except for alpha 6 beta 1 gamma 2 receptors which are less sensitive to the positive allosteric modulation by 3 alpha-OH-DHP [31].

Analytical, diagnostic and therapeutic context of C13712

Perfusion with 5 micrograms/ml of 3 alpha-OH-DHP for 30 min significantly increased the recurrent inhibition evoked by antidromic stimulation [32].
Radioimmunoassay of 3 alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma [33].
3 alpha-Hydroxy-5 alpha-pregnan-20-one was purified from either extracts of plasma by high-performance liquid chromatography [33].
The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) was administered systemically to rats which were tested in the Geller-Seifter conflict paradigm, an established animal model of anxiety [34].
The present experiments investigated the effects of progesterone and its metabolites, dihydryoprogesterone (DHP) and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), to protect the hippocampus from damage induced by adrenalectomy (ADX) [35].

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