neuronal excitability: nootropics and compounds | sci-wiki

Androsterone

Androsterone (3α-hydroxy-5α-androstan-17-one) is an endogenous androstane neurosteroid (a steroid synthesized or acting within the nervous system) and a peripheral metabolite of testosterone and dehydroepiandrosterone. Like its pregnane counterpart allopregnanolone, it acts as a positive allosteric modulator (an agent that enhances a receptor's response to its natural transmitter) of the GABA-A receptor (the brain's principal inhibitory ion channel), producing barbiturate-like potentiation of inhibitory neurotransmission. In rodent studies it raises seizure threshold across multiple models and is regarded as an endogenous modulator of neuronal excitability; because native androsterone is rapidly conjugated and orally poorly available, a prodrug (an inactive precursor that converts to the active drug in the body) has been investigated for epilepsy.

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Neurosteroid

Etiocholanolone

Etiocholanolone (3α-hydroxy-5β-androstan-17-one) is an endogenous androstane neurosteroid formed as a major hepatic metabolite of testosterone and androstenedione. It is the 5-beta epimer of androsterone and acts as a positive allosteric modulator (a compound that amplifies a receptor's response to its own natural ligand) of the GABA-A receptor (the brain's principal inhibitory chloride channel), where it enhances inhibitory neurotransmission and produces anticonvulsant effects in animal seizure models. Etiocholanolone is equally notable in classical human physiology as one of the first identified endogenous pyrogens; injection of the unconjugated steroid reliably produces fever by prompting leukocytes to release interleukin-1. It possesses negligible androgenic activity and circulates largely as biologically inactive glucuronide and sulfate conjugates.

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Neurosteroid

SAGE-324

SAGE-324 (also designated BIIB124) is an investigational, orally bioavailable synthetic neuroactive steroid that acts as a positive allosteric modulator (a compound that amplifies a receptor's response to its natural signal) of GABA-A receptors (the brain's principal inhibitory chloride ion channels). Developed on the Sage Therapeutics neuroactive-steroid platform and co-developed with Biogen, it is a next-generation analog engineered for a long duration of action suitable for once-daily oral dosing, distinguishing it from the intravenous and short-acting neurosteroids that preceded it. Its lead clinical indication is essential tremor (a common movement disorder marked by rhythmic shaking of the hands and arms), where the randomized Phase 2 KINETIC trial met its primary endpoint; it has also been explored in the context of epilepsy. As a synthetic congener within the same chemical lineage as brexanolone and zuranolone, SAGE-324 represents an effort to translate the potent inhibitory pharmacology of endogenous neurosteroids into a chronically dosable oral therapeutic.

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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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