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 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 ...

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 ...

and a

natural Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are part ...

3β-

epimer In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...

allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...

.Öfverman, C., Strömberg, J., Birzniece, V., Turkmen, S., Hill, M., Lundgren, P., ... & Johansson, I. M. (2009). The progesterone metabolite isoallopregnanolone is a subunit-selective antagonist of the GABA-A receptor. Chicago It has been reported to act as a subunit-selective

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 ...

of the GABA_A receptor, and antagonizes in animals and humans some but not all of the GABA_A receptor-mediated effects of allopregnanolone, such as

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 ...

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, ...

, and reduced

saccadic eye movement In vision science, a saccade ( ; ; ) is a quick, simultaneous movement of both eyes between two or more phases of focal points in the same direction. In contrast, in smooth-pursuit movements, the eyes move smoothly instead of in jumps. Control ...

s, but not learning impairment. Isopregnanolone has no

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

effects and appears to have no effect on the GABA_A receptor by itself; it selectively antagonizes allopregnanolone and does not affect the effects of other types of GABA_A receptor

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 ...

s such as

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 or

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

s. Isopregnanolone is synthesized from

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 ...

in the body by the actions of the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s 5α-reductase and 3β-hydroxysteroid dehydrogenase (with 5α-dihydroprogesterone as the intermediate in this two-step transformation) and can be reversibly metabolized into allopregnanolone by the enzyme 3α-hydroxysteroid dehydrogenase. Levels of isopregnanolone, progesterone, and allopregnanolone are highly correlated across the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...

and throughout

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 ...

. The concentrations of isopregnanolone are significantly less than those of progesterone and allopregnanolone; about half of those of allopregnanolone, to be precise. Isopregnanolone has a relatively long serum

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 14 hours in humans. Isopregnanolone (developmental code name UC-1010) is under development for the treatment of

premenstrual dysphoric disorder Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms. PMDD causes significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symp ...

. As of 2017, it is in phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for this indication.

Chemistry

References

External links

Sepranolone - AdisInsight

Sepranolone - Asarina Pharma
{{GABA receptor modulators GABAA receptor negative allosteric modulators Neurosteroids Pregnanes

Chemistry

See also

References

External links