Molecular interactions<unk>  is an endogenous inhibitory pregnane neurosteroid. It is made from progesterone, and is a positive<unk> steric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.<unk>  has effects similar to those of other positive<unk> steric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity. Endogenously produced<unk>  exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive<unk> steric modulators and agonists at GABAA receptor.<unk>  acts as a highly potent positive<unk> steric modulator of the GABAA receptor. While<unk> , like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.<unk>  has also been found to act as a positive<unk> steric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors,<unk> , like progesterone, is known to be a negative<unk> steric modulator of nACh receptors, and also<unk> pears to act as a negative<unk> steric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids,<unk> <unk> pears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors. Unlike progesterone,<unk>  is inactive at the classical nuclear progesterone receptor (PR). However,<unk>  can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason,<unk>  can produce PR-mediated progestogenic effects. In addition,<unk>  was reported in 2012 to be an agonist of the membrane progesterone receptors (mPRs) discovered shortly before, including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor. The action of<unk>  at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties. Also like progesterone, recent evidence has shown that<unk>  is an activator of the pregnane X receptor. Similarly to many other GABAA receptor positive<unk> steric modulators,<unk>  has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs), including α1 subtypes Cav1.2 and Cav1.3. However, the threshold concentration of<unk>  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. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous<unk> . Also,<unk> , 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<unk>  estimated to be present in the brain. Biphasic actions at the GABAA receptor Increased levels of<unk>  can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. This<unk> pears to be because<unk>  possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total<unk> , which are<unk> proximately 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<unk> steric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates<unk>  levels) has been found to have negative effects on mood, while higher doses have a neutral effect. 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<unk>  may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.
Allopregnanolone
Vinyltestosterone
Pregnanolone
Ethinylestradiol sulfonate
Estradiol enantate
Hydroxyprogesterone acetate
Methandriol propionate
Ethinylestradiol