NMDA receptor: nootropics and compounds | sci-wiki

Magnesium L-Threonate

Magnesium L-threonate is a magnesium salt of L-threonic acid, a sugar acid derived from vitamin C. It was developed as a supplemental form intended to raise magnesium levels in the central nervous system more effectively than conventional magnesium salts; unlike most oral forms, it has been shown to increase magnesium in the cerebrospinal fluid and within neurons, where it up-regulates NR2B-containing NMDA receptors and increases the density of functional synapses. In animal studies these actions are associated with improved learning and enhanced retention of fear extinction, and it is studied mainly for possible effects on memory, cognition, sleep, and anxiety. First described in a 2010 laboratory study, it is sold commercially under names such as Magtein.

2 outlets

Nootropic

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

Agmatine

Agmatine is a small biogenic amine produced in the body from the amino acid arginine by the enzyme arginine decarboxylase, and it also occurs in fermented foods. Rather than acting on a single dedicated receptor, it is a neuromodulator that engages several systems at once: it is an endogenous ligand at imidazoline receptors, blocks the open pore of the NMDA glutamate receptor, and inhibits neuronal nitric oxide synthase, in part by acting as a suicide substrate that irreversibly destroys the enzyme's heme. It is studied for possible roles in pain, mood, opioid tolerance, and neuroprotection, and is sold as a dietary supplement in the form of agmatine sulfate.

1 outlet

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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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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Dopaminergic

Amantadine

Amantadine is an adamantane-derived drug that was first introduced in the 1960s as an antiviral agent against influenza A and later found, by chance, to relieve the symptoms of Parkinson's disease. Today it is used mainly in neurology, particularly to treat the involuntary movements (dyskinesias) that can arise from long-term levodopa therapy, while its role against influenza has largely disappeared because of viral resistance. It acts through a combination of dopaminergic and glutamatergic effects on the brain [1][2].

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Blend

Dextromethorphan + Bupropion

Dextromethorphan/bupropion is a fixed-dose combination medicine used to treat major depressive disorder in adults. Sold under the brand name Auvelity and developed by Axsome Therapeutics, it was approved by the United States Food and Drug Administration in 2022. The product pairs dextromethorphan, which blocks NMDA glutamate receptors and activates sigma-1 receptors, with bupropion, an established antidepressant that also slows the breakdown of dextromethorphan so that useful levels are maintained. It is taken as an extended-release oral tablet and is a prescription medicine that is not a controlled substance.

1 outlet

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.

2 outlets

Nootropic

24(S)-Hydroxycholesterol

24(S)-Hydroxycholesterol (historically named cerebrosterol) is an endogenous oxysterol (an oxygenated derivative of cholesterol) generated almost exclusively in neurons by the enzyme cholesterol 24-hydroxylase (CYP46A1). It is the principal chemical route by which the brain, which cannot degrade cholesterol, exports its surplus; because the added hydroxyl group at carbon 24 allows the molecule to cross the blood-brain barrier (the selective interface between blood and brain tissue), plasma levels of 24(S)-hydroxycholesterol serve as an accessible marker of brain cholesterol turnover and neuronal mass. Beyond its housekeeping role, it is a bona fide neurosteroid; at physiological concentrations it acts as a potent positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors (a class of glutamate-gated ion channels central to learning and memory) and as an agonist of liver X receptors (LXR, nuclear receptors that govern lipid handling). Its pharmacology inspired the synthetic analog dalzanemdor (SAGE-718), an NMDA receptor positive allosteric modulator developed for cognitive impairment.

NMDA receptor

Magnesium L-Threonate

Pregnenolone

Agmatine

DHEA

Pregnanolone

Amantadine

Dextromethorphan + Bupropion

Progesterone

24(S)-Hydroxycholesterol

D-Cycloserine

D-Serine

DHEA Sulfate

Epiandrosterone

Epipregnanolone

Gacyclidine

HA-966

Hemantane

Ibogaine

NMDA

Pregnenolone Sulfate

SAGE-718

Traxoprodil

Zelquistinel

Methadone

NMDA receptor

Magnesium L-Threonate

Pregnenolone

Agmatine

DHEA

Pregnanolone

Amantadine

Dextromethorphan + Bupropion

Progesterone

24(S)-Hydroxycholesterol

D-Cycloserine

D-Serine

DHEA Sulfate

Epiandrosterone

Epipregnanolone

Gacyclidine

HA-966

Hemantane

Ibogaine

NMDA

Pregnenolone Sulfate

SAGE-718

Traxoprodil

Zelquistinel

Methadone