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Allopregnanolone

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Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Clinical data
Trade namesZulresso
Other namesALLO; Allo; ALLOP; AlloP; Brexanolone; SAGE-547; SGE-102; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP
Routes of
administration		Intravenous infusion[1]
Drug classNeurosteroids; Antidepressants
Legal status
Legal status
Pharmacokinetic data
Protein binding>99%[1]
MetabolismNon-CYP450 (keto-reduction via AKRs, glucuronidation via UGTs, sulfation via SULTs)[1]
Elimination half-life9 hours[1]
ExcretionFeces: 47%[1]
Urine: 42%[1]
Identifiers
  • 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H34O2
Molar mass318.501 g/mol g·mol−1
3D model (JSmol)
  • 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
  • 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-SYBPFIFISA-N

Allopregnanolone, is a naturally produced steroid that reduces brain activity via GABA A ion channels.[2][3] As a medication, a formulation of allopregnanolone is sold under the brand name Zulresso[4] and used to treat postpartum depression.[3][5][6] It is used by injection into a vein over a 60-hour period under medical supervision.[3]

Allopregnanolone and synthetic variants have pharmacology similar to the barbiturates, acting at GABA A ion channels, with large doses leading to CNS depression and potential death. External dosing of these compounds is also associated with tolerance and self-administration, and as such are considered DEA controlled substances, like benzodiazepines and barbiturates. Side effects of Zulresso may include sleepiness, dry mouth, and loss of consciousness.[1][3] 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).[1]

Zulresso was approved for medical use in the United States in 2019 with commercial sales expected to begin in June 2019.[3][7] The long administration time, as well as the cost of US$34,000, have raised concerns about accessibility for many women.[8]

Side effects of Zulresso may include sleepiness, dry mouth, and loss of consciousness.[1][3] 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).[1]

Zulresso was approved for medical use in the United States in 2019 with commercial sales expected to begin in June 2019.[3][4] The long administration time, as well as the cost of US$34,000, have raised concerns about accessibility for many women.[5]

Medical uses

Brexanolone is used to treat postpartum depression in women.[3]

Side effects

Side effects may include sleepiness, dry mouth, and loss of consciousness.[1][3]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[6] prosocial,[7] antiaggressive,[8] prosexual,[7] sedative, pro-sleep,[9] cognitive, memory-impairment, analgesic,[10] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[11] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.[12][13][14]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.[15][16][17] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[15][16] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[12][17] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[18]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[19][20]

Mechanism of action

It is an endogenous inhibitory pregnane neurosteroid.[11] It is made from progesterone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[11] 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.[11][21][22] 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.[23]

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[11] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.[24] 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.[25][26] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[27] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[28] 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.[29]

Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor (PR).[29] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason, allopregnanolone can produce PR-mediated progestogenic effects.[30][31] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPRs), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[32][33] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[32][34] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[29][35]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[36] including α1 subtypes Cav1.2 and Cav1.3.[37] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[37] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[37] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[38] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[38]

Chemistry

See also: List of neurosteroids

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is very closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[11] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[39]

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[11]

Society and culture

Names

Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid, whereas brexanolone (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name)[40] is the name of the compound formulation in the context of its use as a medication. Zulresso is the brand name of brexanolone as a medication.

Research

Aside from its use in postpartum depression, brexanolone is also under development as an intravenously administered medication for the treatment of super-refractory status epilepticus and essential tremor.[4]

Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[41] Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone.[41] As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy,[42] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone has also been found to act as a prodrug of allopregnanolone,[43][44][45] though also of pregnenolone sulfate.[46]

See also

References

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