Allopregnanolone is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...

which is made in the body from the

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat

postpartum depression Postpartum depression (PPD), also called perinatal depression, is a mood disorder which may be experienced by pregnant or postpartum women. Symptoms include extreme sadness, low energy, anxiety, crying episodes, irritability, and extreme cha ...

. It is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of brexanolone may include

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

sleepiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

dry mouth Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es, and

loss of consciousness Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the re ...

. It is a

and acts as a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the GABA_A receptor, the major

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

of the

inhibitory An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a Chemical synapse, postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Inc ...

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

γ-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(GABA). Brexanolone was approved for medical use in the United States in 2019. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a prototype drug that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medic ...

. The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.

Medical uses

Brexanolone is used to treat postpartum depression in adult women, administered as a continuous

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

over a period of 60 hours, and essential tremor.

Clinical efficacy

Women experiencing moderate to severe postpartum depression when treated with a single dose of intravenous brexanolone display a significant reduction in HAM-D scores which persisted 30 days post-treatment.

Side effects

Side effects of brexanolone include dizziness (10–20%),

(13–21%), headache (18%), nausea (10%), dry mouth (3–11%), loss of consciousness (3–5%), and

flushing Flushing may refer to: Places Netherlands * Flushing, Netherlands, an English name for the city of Vlissingen, Netherlands United Kingdom * Flushing, Cornwall, a village in Cornwall, England * The Flushing, a building in Suffolk, England ...

(2–5%). It can produce

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

to a degree similar to that of

alprazolam Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...

(3–13% at infusion doses of 90–270 μg over a one-hour period). Serious or severe adverse effects are rare but may include

altered state of consciousness An altered state of consciousness (ASC), also called an altered state of mind, altered mental status (AMS) or mind alteration, is any condition which is significantly different from a normal waking state. It describes induced changes in one's me ...

, syncope, presyncope, fatigue, and

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order,

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

, stress-reducing,

rewarding The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and clas ...

prosocial Prosocial behavior is a social behavior that "benefit other people or society as a whole", "such as helping, sharing, donating, co-operating, and volunteering". The person may or may not intend to benefit others; the behavior's prosocial benefi ...

antiaggressive A serenic, or anti-aggressive drug, is a type of drug which reduces the capacity for aggression. Examples Serotonergic agents The recreational drug MDMA ("ecstasy") and a variety of related drugs have been described as ''empathogen-entactogens' ...

prosexual An aphrodisiac is a substance that increases libido, sexual desire, sexual attraction, sexual pleasure, or sexual behavior. These substances range from a variety of plants, spices, and foods to synthetic chemicals. Natural aphrodisiacs, such as ...

, sedative, pro-sleep,

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

, memory-impairment,

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal l ...

, and

neurogenic In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes t ...

effects. Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

premenstrual syndrome Premenstrual syndrome (PMS) is a disruptive set of emotional and physical symptoms that regularly occur in the one to two weeks before the start of each menstrual period. Symptoms resolve around the time menstrual bleeding begins. Symptoms v ...

, catamenial epilepsy, and various other neuropsychiatric conditions. During

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, allopregnanolone and

pregnanolone Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties. Biological activity Pregnanolone is a pos ...

are involved in

and

anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...

of the

fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...

. Allopregnanolone is a

metabolic intermediate Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells. Although these intermediates are of relatively minor direct importance to cell ...

in an

androgen backdoor pathway The androgen backdoor pathway (the backdoor pathway of androgen biosynthesis) is a metabolic route in which androgens are produced from 21-carbon () steroids bypassing testosterone and androstenedione as intermediates. This process starts wi ...

from

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

, which occurs during normal male

development; placental progesterone in the male fetus is the feedstock of this pathway; deficiencies in this pathway lead to insufficient

virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is a medical term commonly used in three medical a ...

of the male fetus.

Mechanism of action

Molecular interactions

Allopregnanolone is an

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

pregnane Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...

. It is

made Made or MADE may refer to: Entertainment Film * ''Made'' (1972 film), United Kingdom * ''Made'' (2001 film), United States Music * ''Made'' (Big Bang album), 2016 * ''Made'' (Hawk Nelson album), 2013 * ''Made'' (Scarface album), 2007 *'' M.A.D.E. ...

from

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...

, and is a

of the action of γ-aminobutyric acid (GABA) at GABA_A receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABA_A receptor such as the

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, including anxiolytic, sedative, and anticonvulsant activity. Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABA_A receptor and modulating the action of several positive allosteric modulators and agonists at GABA_A receptor. Allopregnanolone acts as a highly potent positive allosteric modulator of the GABA_A receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation. Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...

nACh receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

s, and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other

ligand-gated ion channel Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as sodium, Na+, potassium, K+, calcium, Ca2+, and/or chloride, Cl− to ...

s, including the

NMDA ''N''-methyl--aspartic acid, or ''N''-methyl--aspartate (NMDA), is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unl ...

AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate Glutamic acid (symbol Glu or E; kn ...

kainate Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervo ...

, and

glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochem ...

s. Unlike progesterone, allopregnanolone is inactive at the classical

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

(PR). However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the PR, and for this reason, allopregnanolone can produce PR-mediated

progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...

ic effects. ( 5α-dihydroprogesterone is reduced to produce allopregnanolone, and progesterone is reduced to produce 5α-dihydroprogesterone). In addition, allopregnanolone was reported in 2012 to be an agonist of the

membrane progesterone receptor Membrane progesterone receptors (mPRs) are a group of cell surface receptors and membrane steroid receptors belonging to the progestin and adipoQ receptor (PAQR) family which bind the endogenous progestogen and neurosteroid progesterone, as well as ...

s (mPRs) discovered shortly before, including

mPRδ Membrane progesterone receptor delta (mPRδ), or progestin and adipoQ receptor 6 (PAQR6), is a protein that in humans is encoded by the ''PAQR6'' gene. See also * Membrane progesterone receptor * Progestin and adipoQ receptor The progestin and ...

mPRα Membrane progesterone receptor alpha (mPRα), or progestin and adipoQ receptor 7 (PAQR7), is a protein that in humans is encoded by the ''PAQR7'' gene. See also * Membrane progesterone receptor * Progestin and adipoQ receptor The progestin and ...

, and

mPRβ Membrane progesterone receptor beta (mPRβ), or progestin and adipoQ receptor 8 (PAQR8), is a protein that in humans is encoded by the ''PAQR8'' gene. See also * Membrane progesterone receptor * Progestin and adipoQ receptor The progestin and a ...

, with its activity at these receptors about a magnitude more potent than at the GABA_A receptor. The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and

antigonadotropic An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...

properties. Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the

pregnane X receptor In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the ' ...

. Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

of L-type voltage-gated calcium channels (L-VGCCs), including α₁ subtypes Ca_v1.2 and Ca_v1.3. 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. 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 The G protein-coupled bile acid receptor 1 (GPBAR1) also known as G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or Takeda G protein-coupled receptor 5 (TGR5) is a protein that in humans is encoded by the '' ...

(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 GABA_A receptor

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety,

irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...

, and

aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...

. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to

luteal phase The menstrual cycle is on average 28 days in length. It begins with Menstruation, menses (day 1–7) during the follicular phase (day 1–14), followed by ovulation (day 14) and ending with the luteal phase (day 14–28). While historically, medi ...

levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABA_A receptor positive allosteric modulators. In accordance, acute administration of low doses of

micronized progesterone Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms a ...

(which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.

Antidepressant effects

The mechanism by which neurosteroid GABA_A receptor positive allosteric modulators (PAMs) like brexanolone have antidepressant effects is unknown. Other GABA_A receptor PAMs, such as

s, are not thought of as antidepressants and have no proven efficacy, although

has historically been prescribed for depression. Neurosteroid GABA_A receptor PAMs are known to interact with GABA_A receptors and subpopulations differently than benzodiazepines. GABA_A receptor-potentiating neurosteroids may preferentially target δ-subunit–containing GABA_A receptors, and enhance both tonic and phasic inhibition mediated by GABA_A receptors. It is possible that neurosteroids like allopregnanolone may act on other

target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...

s, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.

Pharmacology

Pharmacokinetics

Brexanolone has low

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of less than 5%, necessitating non-oral administration. The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of brexanolone is approximately 3 L/kg. Its

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

is more than 99%. Brexanolone is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

by keto- reduction mediated via

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, x ...

s. The compound is conjugated by

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

via

glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...

s and

sulfation Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...

via

sulfotransferase In biochemistry, sulfotransferases (SULTs) are transferase enzymes that catalyze the transfer of a sulfo group () from a donor molecule to an acceptor alcohol () or amine (). The most common sulfo group donor is 3'-phosphoadenosine-5'-phosphos ...

s. It is not metabolized significantly by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

system. The three main

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of brexanolone are inactive. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of brexanolone is nine hours. Its total plasma clearance is 1 L/h/kg. It is

excreted Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific ...

47% in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

and 42% in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. Less than 1% is excreted as unchanged brexanolone.

Chemistry

Allopregnanolone is a pregnane (C21)

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

and is also known as 5α-pregnan-3α-ol-20-one, 5α-pregnane-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of

pregnanedione Pregnanedione, or pregnane-3,20-dione, may refer to: * 5α-Dihydroprogesterone (5α-pregnane-3,20-dione) * 5β-Dihydroprogesterone (5β-pregnane-3,20-dione) See also * Progesterone Progesterone (; P4) is an endogenous steroid and progestog ...

(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 Pregnanediol, or 5β-pregnane-3α,20α-diol, is an inactive metabolic product of progesterone. A test can be done to measure the amount of pregnanediol in urine, which offers an indirect way to measure progesterone levels in the body. From the ur ...

(5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of

(3,5-tetrahydroprogesterone), with the other three isomers being

(5β-pregnan-3α-ol-20-one),

isopregnanolone Isopregnanolone, also known as isoallopregnanolone and epiallopregnanolone, as well as sepranolone (), and as 3β-hydroxy-5α-pregnan-20-one or 3β,5α-tetrahydroprogesterone (3β,5α-THP), is an endogenous neurosteroid and a natural 3β-epimer of ...

(5α-pregnan-3β-ol-20-one), and

epipregnanolone Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiator ...

(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. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone. Allopregnanolone in the brain is produced by cortical and

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

pyramidal neuron Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cort ...

s and pyramidal-like neurons of the

basolateral amygdala The basolateral amygdala, or basolateral complex, or basolateral nuclear complex consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly fr ...

Derivatives

A variety of

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

derivatives and

analogues ''Analogues'' (Spanish: ''Análogos'') is a 2023 Chilean science fiction drama film written, scored and directed by Jorge Olguín. Starring Mónica Carrasco and Jorge Gajardo accompanied by Cindy Díaz. It is about an elderly couple who feel alone ...

of allopregnanolone with similar activity and effects exist, including

alfadolone Alfadolone ( INN), or alphadolone is a neuroactive steroid and general anesthetic. Along with alfaxolone, as alfadolone acetate, it is one of the components of the anesthetic drug mixture althesin. Chemistry See also * Ganaxolone * Hydr ...

(3α,21-dihydroxy-5α-pregnane-11,20-dione),

alfaxolone Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable ...

(3α-hydroxy-5α-pregnane-11,20-dione),

ganaxolone Ganaxolone, sold under the brand name Ztalmy, is a medication used to treat seizures in people with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Ganaxolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor pos ...

(3α-hydroxy-3β-methyl-5α-pregnan-20-one),

hydroxydione Hydroxydione, as hydroxydione sodium succinate (, , ) (brand names Viadril, Predion, and Presuren), also known as 21-Hydroxy-5β-pregnane-3,20-dione, is a neuroactive steroid which was formerly used as a general anesthetic, but was discontinued d ...

(21-hydroxy-5β-pregnane-3,20-dione),

minaxolone Minaxolone (CCI-12923) is a neuroactive steroid which was developed as a general anesthetic but was withdrawn before registration due to toxicity seen with long-term administration in rats, and hence was never marketed. It is a positive allosteri ...

(11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one),

Org 20599 ORG-20599 is a synthetic neuroactive steroid, with sedative effects resulting from its action as a GABAA receptor positive allosteric modulator and, at higher concentrations, agonist An agonist is a chemical that activates a Receptor (biochemi ...

(21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one),

Org 21465 ORG-21465 is a synthetic neuroactive steroid, with sedative effects resulting from its action as a GABAA receptor positive allosteric modulator. It is similar to related drugs such as ORG-20599, and was similarly developed as an improved altern ...

(2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and

renanolone Renanolone (International Nonproprietary Name, INN), or 11-ketopregnanolone, also known as 5β-pregnan-3α-ol-11,20-dione, is a synthetic compound, synthetic neuroactive steroid which is described as a general anesthetic but was never introduced ...

(3α-hydroxy-5β-pregnan-11,20-dione). The 21-hydroxylated derivative of this compound,

tetrahydrodeoxycorticosterone Tetrahydrodeoxycorticosterone (abbreviated as THDOC; 3α,21-dihydroxy-5α-pregnan-20-one), also referred to as ''allotetrahydrocorticosterone'', is an endogenous neurosteroid. It is synthesized from the adrenal hormone deoxycorticosterone by the ...

, 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 Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

and other conditions, including

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

History

In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women, the first drug approved by the U.S.

(FDA) specifically for PPD. The efficacy of brexanolone was shown in two clinical studies of participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks. The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression. The FDA granted the application for brexanolone

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

and

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "b ...

designations, and granted approval of Zulresso to Sage Therapeutics, Inc.

Society and culture

Names

Brexanolone is both the International Nonproprietary Name and the

United States Adopted Name A United States Adopted Name (USAN) is a unique nonproprietary name assigned to a medication marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United St ...

in the context of its use as a medication. Zulresso is a brand name of the medication.

Legal status

In the United States, brexanolone is a Schedule IV

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

Available forms

Brexanolone is an

aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, also known as sodium chloride (NaCl), in wat ...

mixture In chemistry, a mixture is a material made up of two or more different chemical substances which can be separated by physical method. It is an impure substance made up of 2 or more elements or compounds mechanically mixed together in any proporti ...

of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent. It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose

vial A vial (also known as a phial or flacon) is a small glass or plastic vessel or bottle, often used to store medication in the form of liquids, powders, or capsules. They can also be used as scientific sample vessels; for instance, in autosam ...

s for use by intravenous infusion. Each mL of brexanolone solution contains 5 mg allopregnanolone, 250 mg sulfobutyl ether β-cyclodextrin, 0.265 mg citric acid monohydrate, 2.57 mg sodium citrate dihydrate, and

water for injection Water for injection is water of extra high quality without significant contamination. A sterile version is used for making solutions that will be given by injection. Before such use other substances generally must be added to make the solution ...

. The solution is

hypertonic In chemical biology, tonicity is a measure of the effective osmotic pressure gradient; the water potential of two solutions separated by a partially-permeable cell membrane. Tonicity depends on the relative concentration of selective membran ...

and must be diluted to a target concentration of 1 mg/mL with sterile water and

sodium chloride Sodium chloride , commonly known as Salt#Edible salt, edible salt, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is transparent or translucent, brittle, hygroscopic, and occurs a ...

prior to administration. Five infusion bags are generally required for the full infusion. More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs).

Research

Brexanolone was under development as an intravenously administered medication for the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

super-refractory status epilepticus Status epilepticus (SE), or status seizure, is a medical condition with abnormally prolonged seizures. It can have long-term consequences, manifesting as a single seizure lasting more than a defined time (time point 1), or 2 or more seizures over ...

, and

essential tremor Essential tremor (ET), also called benign tremor, familial tremor, and idiopathic tremor, is a medical condition characterized by involuntary rhythmic contractions and relaxations ( oscillations or twitching movements) of certain muscle groups i ...

, but development for these indications was discontinued. It has been suggested that allopregnanolone and its precursor pregnenolone may have therapeutic potential for treatment of various symptoms of alcohol use disorders by restoring deficits in GABAergic inhibition, moderating corticotropin releasing factor (CRF) signaling, and inhibiting excessive neuroimmune activation. Many co-occurring symptoms of ethanol addiction (e.g., anxiety, depression, seizures, sleep disturbance, pain) that are believed to contribute to the downward spiral of the addiction may also be controlled with

neuroactive steroids Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...

Exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

progesterone, such as

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 A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

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

has also been found to act as a prodrug of allopregnanolone, though also of

pregnenolone sulfate Pregnenolone sulfate (PS, PREGS) is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects. Biological activi ...

. In animal models of

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...

, allopregnanolone has been shown to reduce inflammation by attenuating the production of proinflammatory cytokines (IL-1β and TNF-α) at 3 h after the injury. It has also been shown to reduce the severity of brain damage and improve cognitive function and recovery.

References

External links

* * * {{Portal bar , Medicine Anticonvulsants Antidepressants GABAA receptor positive allosteric modulators GABAA-rho receptor positive allosteric modulators Glycine receptor agonists Acetyl compounds Neurosteroids Nicotinic antagonists Pregnane X receptor agonists Pregnanes 5α-Pregnanes Progestogens Sterols

Medical uses

Clinical efficacy

Side effects

Biological function

Mechanism of action

Molecular interactions

Biphasic actions at the GABAA receptor

Antidepressant effects

Pharmacology

Pharmacokinetics

Chemistry

Biosynthesis

Derivatives

History

Society and culture

Names

Legal status

Available forms

Research

See also

References

Further reading

External links

Biphasic actions at the GABA_A receptor