trpm3 channel: 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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Neurosteroid

Epipregnanolone

Epipregnanolone (3beta-hydroxy-5beta-pregnan-20-one) is an endogenous neurosteroid and the fourth stereoisomer of tetrahydroprogesterone, distinguished from allopregnanolone (3alpha,5alpha), pregnanolone (3alpha,5beta), and sepranolone (3beta,5alpha) by its combined 3beta-hydroxyl group and 5beta (cis) ring fusion. It is a ring A-reduced metabolite of progesterone that, unlike the sedative potentiators allopregnanolone and pregnanolone, was classically characterized as a selective antagonist at the neurosteroid modulatory site of the GABA-A receptor (the brain's principal inhibitory ion channel), blocking their potentiation without altering the response to GABA itself. Its 3-sulfate ester is a negative allosteric modulator of the NMDA receptor (a glutamate-gated excitatory channel), and the parent steroid is also a potent blocker of CaV3.2 T-type calcium channels, giving it a profile that is unusually distinct from its potentiating sister isomers. Present at low concentrations in human plasma, especially around parturition, and producible by human gut bacteria, epipregnanolone is studied primarily as a pharmacological tool and a scaffold for neurosteroid drug design rather than as a therapeutic or supplement.

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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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