sigma-1 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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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

DHEA Sulfate

DHEA sulfate (DHEAS) is the 3-beta sulfate ester of dehydroepiandrosterone and the most abundant circulating steroid in the human body, present in plasma at concentrations roughly a thousandfold higher than unconjugated DHEA. Synthesized principally in the zona reticularis of the adrenal cortex, it functions as a stable, long-lived reservoir that is interconverted with DHEA and supplies a precursor pool for downstream androgens and estrogens. Within the nervous system it is classified as a neurosteroid (a steroid synthesized in or acting directly upon nervous tissue); it acts as an agonist at the sigma-1 receptor (an intracellular chaperone protein), a positive modulator of the NMDA receptor (a glutamate-gated excitatory ion channel), and a negative allosteric modulator of the GABA-A receptor (the brain's principal inhibitory ion channel), giving it a net excitatory, pro-cognitive neuromodulatory profile. Circulating concentrations fall markedly with age, a decline termed adrenopause that has made DHEAS a widely studied biomarker of adrenal function, cognitive aging, and longevity.

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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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Nootropic

Methylphenylpiracetam

Methylphenylpiracetam (MPP) is a methylated analogue of phenylpiracetam developed at the Latvian Institute of Organic Synthesis, and its most studied stereoisomer, E1R, is a positive allosteric modulator of the sigma-1 receptor [1]. In mice, E1R enhances memory retention and reverses scopolamine-induced cognitive impairment without altering locomotor activity, effects abolished by the selective sigma-1 antagonist NE-100 [1]. Unlike its parent phenylpiracetam, which is primarily a dopaminergic psychostimulant, MPP is characterized as a non-stimulant cognition enhancer acting through sigma-1 chaperone signaling [1].

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Neuroprotection

PRE-084

PRE-084 is a synthetic, highly selective agonist of the sigma-1 receptor, an endoplasmic reticulum chaperone protein that modulates calcium signaling, neurotrophic factor expression, and cellular stress responses. It is used almost exclusively as a preclinical research tool, where it has produced neurorestorative effects in models of Parkinson disease [1], motor neuron survival in models of amyotrophic lateral sclerosis [2], and antidepressant and anti-amnesic activity [5]. A recurring theme across studies is upregulation of brain-derived neurotrophic factor (BDNF) and downstream trophic pathways [2][3][4].

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Nootropic

Pregnenolone Sulfate

Pregnenolone sulfate (PregS) is an endogenous excitatory neurosteroid (a steroid synthesized in and acting upon the nervous system) formed by sulfation of pregnenolone at its 3beta-hydroxyl group. It is among the most intensively studied neurosteroids in ion-channel pharmacology, acting simultaneously as a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors that contain GluN2A or GluN2B subunits (the principal glutamate-gated channels underlying synaptic plasticity), a negative allosteric modulator of GABA-A receptors (the brain's main inhibitory chloride channels), a low-affinity agonist of the sigma-1 receptor (an intracellular chaperone protein) and the prototypical agonist of the TRPM3 cation channel. Through these convergent actions it enhances glutamatergic transmission, hippocampal acetylcholine release, long-term potentiation and memory consolidation in animal models, which underlies its reputation as a pro-cognitive neurosteroid. Its physiological concentrations, and even its unambiguous presence in mammalian brain, remain debated, so much of the evidence base derives from experimental administration rather than demonstrated endogenous signaling.

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Antidepressant

SOMCL-668

SOMCL-668 is the first selective and potent positive allosteric modulator of the sigma-1 receptor, developed by the Shanghai Institute of Materia Medica and characterised at Soochow University. Rather than directly activating the receptor, it amplifies the effects of sigma-1 receptor agonists, and in preclinical models it produces rapid antidepressant, anti-seizure, antipsychotic-like and neuroprotective effects [1][2][3].

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