5-alpha-reductase pathway: nootropics and compounds | sci-wiki

Allopregnanolone

Allopregnanolone (chemically 3-alpha-hydroxy-5-alpha-pregnan-20-one, also known as 3-alpha,5-alpha-tetrahydroprogesterone or 3-alpha,5-alpha-THP) is an endogenous neurosteroid synthesized in the brain, adrenal glands and gonads as a downstream metabolite of the hormone progesterone. It is the prototypical inhibitory neuroactive steroid and one of the most potent known positive allosteric modulators (molecules that amplify a receptor's response to its natural transmitter) of the GABA-A receptor (the brain's principal inhibitory chloride ion channel), acting at both synaptic receptors and extrasynaptic delta-subunit-containing receptors. The pharmaceutical formulation of this exact molecule, brexanolone (trade name Zulresso), became in 2019 the first drug ever approved by the United States Food and Drug Administration specifically for postpartum depression, and its orally active analog zuranolone followed in 2023. Beyond its rapid actions on inhibitory neurotransmission, allopregnanolone participates in the stress response, ovarian-cycle and pregnancy physiology, seizure regulation and, as more recently characterized, the suppression of innate-immune inflammatory signaling.

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Nootropic

Epiandrosterone

Epiandrosterone (3β-hydroxy-5α-androstan-17-one; also called isoandrosterone) is an endogenous 5-alpha-reduced steroid formed from dehydroepiandrosterone (DHEA) and androstenedione, and it is the 3-beta-hydroxyl epimer of androsterone. It circulates in humans predominantly as its sulfate ester and functions as a weak neurosteroid (a steroid that acts on neuronal receptors rather than classical nuclear hormone receptors), producing only mild modulation of the GABA-A receptor (the brain's principal inhibitory chloride ion channel) while inhibiting glycine receptors (another inhibitory ligand-gated channel concentrated in the spinal cord and brainstem). Beyond the nervous system it is a well-characterized uncompetitive inhibitor of glucose-6-phosphate dehydrogenase (G6PD, the rate-limiting enzyme of the pentose phosphate pathway) and a recognized urinary marker of 5-alpha-reductase activity. Because it can be metabolized toward dihydrotestosterone (DHT, the most potent natural androgen), it is also sold over the counter as a non-methylated androgen prohormone.

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Neurosteroid

THDOC

THDOC (3-alpha,5-alpha-tetrahydrodeoxycorticosterone) is an endogenous neurosteroid (a steroid that acts rapidly on neuronal membrane receptors rather than on classical nuclear hormone receptors) and the fully reduced 3-alpha,5-alpha metabolite of the adrenal steroid deoxycorticosterone. It is one of the most potent naturally occurring positive allosteric modulators (compounds that amplify a receptor's response to its own transmitter) of the GABA-A receptor, the brain's principal inhibitory chloride ion channel, where it enhances both fast synaptic and sustained extrasynaptic inhibition. Because its synthesis is driven by adrenocorticotropic hormone and by acute stress, THDOC is regarded as a stress-responsive inhibitory neurosteroid that provides negative feedback on the hypothalamic-pituitary-adrenal axis and transiently raises the seizure threshold. Alongside allopregnanolone, it is a prototypical member of the stress-derived GABAergic neurosteroid family.

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