gaba-a receptor: nootropics and compounds | sci-wiki

Pregnenolone

Pregnenolone (3β-hydroxypregn-5-en-20-one) is an endogenous neurosteroid and the first steroid synthesized from cholesterol, making it the obligatory precursor of every other steroid hormone, including progesterone, dehydroepiandrosterone (DHEA), cortisol, the sex steroids, and the neuroactive metabolites allopregnanolone and pregnenolone sulfate. Once regarded as a metabolically inert intermediate, it is now recognized as a signaling molecule in its own right, most notably as an endogenous negative allosteric modulator of the type-1 cannabinoid receptor (CB1, the principal brain receptor for THC) and as a ligand for microtubule-associated protein 2 (MAP2, a neuronal cytoskeletal scaffolding protein), through which it promotes microtubule assembly and neurite outgrowth. Synthesized de novo in the brain by neurons and glia, it is investigated as an adjunctive treatment for schizophrenia, mood disorders, and cannabis-related conditions, and is sold over the counter as a nootropic and hormonal supplement.

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Nootropic

DHEA

Dehydroepiandrosterone (DHEA) is an endogenous androstane neurosteroid and the most abundant circulating steroid hormone in humans, secreted chiefly by the adrenal cortex and also synthesized de novo within the central nervous system. It functions primarily as a precursor to androgens and estrogens, yet exerts direct actions on the brain by acting as an agonist at the sigma-1 receptor (an endoplasmic reticulum chaperone protein that shapes calcium and neurotrophic signaling), as a positive modulator of NMDA receptor (the principal excitatory glutamate ion channel involved in learning) signaling, and, chiefly as its sulfate ester DHEAS, as a negative allosteric modulator of the GABA-A receptor (the brain's main inhibitory ion channel). DHEA additionally behaves as a functional anti-glucocorticoid, buffering the neurotoxic effects of cortisol, and shows neuroprotective and mood-related activity in preclinical and clinical studies. Circulating concentrations peak in early adulthood and decline markedly with age, a phenomenon termed adrenopause that has driven its widespread use as an over-the-counter supplement.

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Nootropic

Etifoxine

Etifoxine (brand name Stresam; also called etafenoxine) is a benzoxazine anxiolytic (an anti-anxiety drug from a chemical family unrelated to the benzodiazepines like Valium). It has been prescribed for the anxious, tense, physical side of stress mainly in France and a handful of other countries since the late 1970s, and it is not approved by the US FDA. What makes it interesting is a dual mechanism: it calms the brain both by directly tuning up GABA-A receptors and by nudging the body to make more of its own calming neurosteroids. In head-to-head trials it eased anxiety comparably to some benzodiazepines while causing less sedation, less memory and psychomotor impairment, and little rebound or dependence when stopped. It has also been explored beyond anxiety for helping injured peripheral nerves heal and for damping neuroinflammation (inflammation inside nervous tissue). The important caveat is safety: rare but serious liver injury and severe skin reactions have been reported.

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Neurosteroid

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

Progesterone

Progesterone (P4; pregn-4-ene-3,20-dione) is an endogenous pregnane steroid hormone best known for its reproductive roles and is the prototypical neuroactive precursor within the neurosteroid system. Although the parent hormone signals principally through classical nuclear progesterone receptors and through membrane-associated receptors such as PGRMC1 and the mPR/PAQR family, most of its rapid effects on neuronal excitability arise only after sequential metabolism to 5-alpha-dihydroprogesterone and then to allopregnanolone, one of the most potent endogenous positive allosteric modulators of the GABA-A receptor (the brain's principal inhibitory chloride channel). Progesterone and its metabolites are synthesized within the nervous system itself, where they regulate myelination, neuronal survival, neuroinflammation, and inhibitory tone. It has been studied extensively as a neuroprotective agent, with strong preclinical support but negative large-scale human trials in acute traumatic brain injury.

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Nootropic

3α-Androstanediol

3α-Androstanediol (5α-androstane-3α,17β-diol) is an endogenous neurosteroid formed as the terminal 3α-reduced metabolite of dihydrotestosterone (DHT, the most potent natural androgen). Despite its androgenic origin it binds the androgen receptor only weakly; its defining pharmacology is potent positive allosteric modulation of the GABA-A receptor (the brain's principal inhibitory chloride ion channel), which produces anxiolytic (anxiety-reducing) and anticonvulsant (seizure-suppressing) effects in animal models. It is widely regarded as the androgenic counterpart of allopregnanolone (the analogous progesterone-derived neurosteroid), and is proposed to mediate much of the influence that testosterone exerts on seizure threshold, anxiety, and mood in males. It additionally acts as a ligand of estrogen receptor beta (ERβ), which may underlie some of its cognitive and neuroprotective actions.

gaba-a receptor

Pregnenolone

DHEA

Etifoxine

Pregnanolone

Progesterone

3α-Androstanediol

5α-Dihydroprogesterone

Alfaxalone

Allopregnanolone

Allotetrahydrocorticosterone

Alphadolone

Androstenol

Androsterone

Deoxycorticosterone

DHEA Sulfate

Emapunil

Epiandrosterone

Epipregnanolone

Etiocholanolone

Ganaxolone

Homotaurine

Hydroxydione

Minaxolone

Org 20599

Org 21465

Pregnenolone Sulfate

Renanolone

SAGE-324

Sepranolone

THDOC

Zuranolone

Zaleplon

gaba-a receptor

Pregnenolone

DHEA

Etifoxine

Pregnanolone

Progesterone

3α-Androstanediol

5α-Dihydroprogesterone

Alfaxalone

Allopregnanolone

Allotetrahydrocorticosterone

Alphadolone

Androstenol

Androsterone

Deoxycorticosterone

DHEA Sulfate

Emapunil

Epiandrosterone

Epipregnanolone

Etiocholanolone

Ganaxolone

Homotaurine

Hydroxydione

Minaxolone

Org 20599

Org 21465

Pregnenolone Sulfate

Renanolone

SAGE-324

Sepranolone

THDOC

Zuranolone

Zaleplon