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Alfaxalone

Alfaxalone (also spelled alphaxalone) is a synthetic neuroactive steroid of the pregnane class that produces general anesthesia by acting as a positive allosteric modulator (a molecule that amplifies a receptor's response to its own neurotransmitter) at the GABA-A receptor, the principal inhibitory ion channel of the central nervous system. First introduced in 1971 as the main active component of the intravenous anesthetics Althesin (human) and Saffan (veterinary), it was withdrawn from human use in the 1980s because the solubilizing vehicle Cremophor EL provoked anaphylactoid reactions, then reintroduced in a cyclodextrin formulation marketed for veterinary anesthesia as Alfaxan. Because it lacks classical hormonal activity yet retains rapid, non-cumulative central depressant effects, alfaxalone occupies a distinct pharmacological niche among intravenous anesthetics and now serves as a template for a new generation of water-soluble neurosteroid sedatives such as Phaxan.

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Anesthetic

Alphadolone

Alphadolone (alfadolone; clinically alphadolone acetate) is a synthetic neuroactive pregnane steroid (a laboratory-made steroid that acts on the nervous system) which potentiates the GABA-A receptor, the brain's principal fast inhibitory chloride channel, to produce sedation and anaesthesia. It is best known as the minor component of the intravenous anaesthetic Althesin (for humans) and Saffan (for animals), where it was combined with the more potent alfaxalone in a 3:1 ratio, added chiefly to improve the poor water solubility of alfaxalone while still contributing roughly half of that agent's anaesthetic potency in its own right. Both preparations were dissolved in the surfactant Cremophor EL, whose tendency to trigger histamine release and anaphylactoid reactions led to the withdrawal of Althesin from human use in 1984. Alphadolone later attracted independent research interest because, unlike alfaxalone, it produces spinally mediated analgesia without sedation when given by mouth or intraperitoneally, an effect thought to depend on an analgesic metabolite formed in the liver.

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Neurosteroid

Epipregnanolone

Epipregnanolone (3beta-hydroxy-5beta-pregnan-20-one) is an endogenous neurosteroid and the fourth stereoisomer of tetrahydroprogesterone, distinguished from allopregnanolone (3alpha,5alpha), pregnanolone (3alpha,5beta), and sepranolone (3beta,5alpha) by its combined 3beta-hydroxyl group and 5beta (cis) ring fusion. It is a ring A-reduced metabolite of progesterone that, unlike the sedative potentiators allopregnanolone and pregnanolone, was classically characterized as a selective antagonist at the neurosteroid modulatory site of the GABA-A receptor (the brain's principal inhibitory ion channel), blocking their potentiation without altering the response to GABA itself. Its 3-sulfate ester is a negative allosteric modulator of the NMDA receptor (a glutamate-gated excitatory channel), and the parent steroid is also a potent blocker of CaV3.2 T-type calcium channels, giving it a profile that is unusually distinct from its potentiating sister isomers. Present at low concentrations in human plasma, especially around parturition, and producible by human gut bacteria, epipregnanolone is studied primarily as a pharmacological tool and a scaffold for neurosteroid drug design rather than as a therapeutic or supplement.

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