progesterone metabolism: nootropics and compounds | sci-wiki

Pregnanolone

Pregnanolone (3α-hydroxy-5β-pregnan-20-one, also written 3α,5β-tetrahydroprogesterone) is an endogenous neurosteroid, meaning a steroid that acts rapidly on neuronal ion channels rather than through classical intracellular hormone receptors, formed as a reduced metabolite of progesterone. It is the 5β epimer of allopregnanolone and a potent positive allosteric modulator of the GABA-A receptor (the pentameric chloride channel that carries most fast inhibitory signalling in the brain), giving it sedative, anxiolytic, anticonvulsant and anaesthetic properties. Under the International Nonproprietary Name eltanolone it was developed in the 1990s as an intravenous general anaesthetic, formulated in a soybean-oil emulsion after earlier castor-oil-solubilised steroid anaesthetics proved allergenic; smooth induction and cardiovascular stability were offset by slow recovery and skin reactions, and it was never marketed. Its sulfate and synthetic glutamate esters are studied separately as use-dependent inhibitors of the NMDA receptor, an excitatory glutamate channel implicated in excitotoxicity and neuroprotection.

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Hormone

6-Ketoprogesterone

6-Ketoprogesterone (systematic name pregn-4-ene-3,6,20-trione) is a synthetic oxidised derivative and minor oxidative metabolite of progesterone in which an additional ketone (a carbonyl group) is introduced at the sixth carbon of the steroid B-ring. First isolated from perfused human placentae in 1956 and characterised pharmacologically in Japan in 1958, it is notable for having lost the classical progestational activity of its parent hormone while retaining a weaker, progesterone-like depressant action on the central nervous system. Today it exists chiefly as a pharmacopeial reference standard (a purified compound used to calibrate analytical assays), as a mechanistic probe for the C6 oxidation of progesterone, and as a metabolic curiosity of pregnancy endocrinology. Its status as a genuinely endogenous neurosteroid remains uncertain, so it is treated conservatively as non-endogenous.

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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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