Brexanolone was approved for medical use in the United States in 2019 with commercial sales expected to begin in June 2019. The long administration time, as well as the cost of US$34,000, have raised concerns about accessibility for many women.
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), including ?1 subtypesCav1.2 and Cav1.3. However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 ?M (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. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5). 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.
Biphasic actions at the GABAA receptor
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. 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 nmol/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. This seems to be a common effect of many GABAA receptor positive allosteric modulators. 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.
The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benzodiazepines, are not known to have antidepressant effects. 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 ? 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 is a pregnane (C21) steroid and is also known as 5?-pregnan-3?-ol-20-one, 3?-hydroxy-5?-pregnan-20-one, or 3?,5?-tetrahydroprogesterone (3?,5?-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3?-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 (5?-pregnan-3?-ol-20-one), isopregnanolone (5?-pregnan-3?-ol-20-one), and epipregnanolone (5?-pregnan-3?-ol-20-one).
A variety of syntheticderivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3?,21-dihydroxy-5?-pregnane-11,20-dione), alfaxolone (3?-hydroxy-5?-pregnane-11,20-dione), ganaxolone (3?-hydroxy-3?-methyl-5?-pregnan-20-one), hydroxydione (21-hydroxy-5?-pregnane-3,20-dione), minaxolone (11?-(dimethylamino)-2?-ethoxy-3?-hydroxy-5?-pregnan-20-one), Org 20599 (21-chloro-3?-hydroxy-2?-morpholin-4-yl-5?-pregnan-20-one), Org 21465 (2?-(2,2-dimethyl-4-morpholinyl)-3?-hydroxy-11,20-dioxo-5?-pregnan-21-yl methanesulfonate), and renanolone (3?-hydroxy-5?-pregnan-11,20-dione).
Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid. Brexanolone is both the INN and USAN in the context of its use as a medication.
It is administered continuously by intravenous infusion over a period of 60 hours (2.5 days). The dosage of brexanolone is progressively adjusted over a range of 30 to 90 ?g/kg/hour during this period.
Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations. Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone. As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy, 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, though also of pregnenolone sulfate.
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