Seizure threshold: nootropics and compounds | sci-wiki

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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Anticonvulsant

Lamotrigine

Lamotrigine is a prescription anticonvulsant of the phenyltriazine class that is also widely used as a mood stabilizer. In epilepsy it treats several seizure types, including focal and generalized seizures and those of Lennox-Gastaut syndrome, and in psychiatry it is approved for the long-term maintenance of bipolar I disorder, where it is aimed particularly at preventing depressive episodes. It works mainly by calming overexcited nerve cells, and it is included on the World Health Organization's list of essential medicines.

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Anticonvulsant

Sodium Valproate

Sodium valproate is the sodium salt of valproic acid and one of the principal forms of the drug valproate, a widely used anticonvulsant and mood stabilizer. It is prescribed for several types of epilepsy, for the manic phase of bipolar disorder, and for the prevention of migraine. Valproate carries strong warnings because it can cause serious birth defects and developmental problems when taken during pregnancy.

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Blend

Sodium Valproate + Valproic Acid

Sodium valproate combined with valproic acid is the formulation known as valproate semisodium or divalproex sodium, sold chiefly under the brand name Depakote. It is a stable one-to-one complex of the two forms that dissociates in the gut to release the same active valproate ion. It is used as an anticonvulsant and mood stabilizer, most notably for the manic episodes of bipolar disorder, and is often chosen for its gentler effect on the stomach.

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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.

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Neurosteroid

Allopregnanolone

Allopregnanolone (chemically 3-alpha-hydroxy-5-alpha-pregnan-20-one, also known as 3-alpha,5-alpha-tetrahydroprogesterone or 3-alpha,5-alpha-THP) is an endogenous neurosteroid synthesized in the brain, adrenal glands and gonads as a downstream metabolite of the hormone progesterone. It is the prototypical inhibitory neuroactive steroid and one of the most potent known positive allosteric modulators (molecules that amplify a receptor's response to its natural transmitter) of the GABA-A receptor (the brain's principal inhibitory chloride ion channel), acting at both synaptic receptors and extrasynaptic delta-subunit-containing receptors. The pharmaceutical formulation of this exact molecule, brexanolone (trade name Zulresso), became in 2019 the first drug ever approved by the United States Food and Drug Administration specifically for postpartum depression, and its orally active analog zuranolone followed in 2023. Beyond its rapid actions on inhibitory neurotransmission, allopregnanolone participates in the stress response, ovarian-cycle and pregnancy physiology, seizure regulation and, as more recently characterized, the suppression of innate-immune inflammatory signaling.

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Neurosteroid

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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Anticonvulsant

Bamaluzole

Bamaluzole is an experimental anticonvulsant from the imidazopyridine chemical class, patented by Merck as a potential seizure treatment but never marketed.

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Neurosteroid

Deoxycorticosterone

Deoxycorticosterone (11-deoxycorticosterone, 21-hydroxyprogesterone; also called cortexone or desoxycortone) is an endogenous steroid hormone made by the adrenal cortex that functions both as a mineralocorticoid and as the metabolic precursor to a potent neurosteroid. Acting through the mineralocorticoid receptor (a ligand-activated transcription factor that governs sodium and water balance), it promotes renal salt retention with an affinity close to that of aldosterone. Its principal relevance to neuropharmacology is as the parent compound of 3-alpha,5-alpha-tetrahydrodeoxycorticosterone (THDOC), a positive allosteric modulator of the GABA-A receptor (the brain's main inhibitory chloride channel) that is released during stress and shapes seizure threshold, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis activity. Deoxycorticosterone should not be confused with the psychedelic amphetamine also abbreviated DOC (2,5-dimethoxy-4-chloroamphetamine), which is an entirely unrelated compound.

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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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Anticonvulsant

Ganaxolone

Ganaxolone (research code CCD-1042; brand name Ztalmy) is a synthetic neuroactive steroid, specifically the 3-beta-methyl analog of the endogenous neurosteroid allopregnanolone (a metabolite of progesterone). It is a positive allosteric modulator (a molecule that amplifies a receptor's response to its natural activator) of the GABA-A receptor, the brain's principal inhibitory chloride channel, and it enhances both synaptic (phasic) and extrasynaptic (tonic) inhibition, with particularly strong activity at delta-subunit-containing receptors. In March 2022 it became the first medicine approved by the United States Food and Drug Administration for seizures associated with CDKL5 deficiency disorder (a rare genetic developmental and epileptic encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 gene), and the first synthetic neurosteroid approved as an anticonvulsant. The defining 3-beta-methyl group makes ganaxolone orally bioavailable, metabolically stable, and non-hormonal, distinguishing it from its parent neurosteroid, which requires intravenous administration.

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Nootropic

PF-06827443

PF-06827443 is a Pfizer M1-selective positive allosteric modulator designed to test whether M1 modulation without agonist activity could avoid cholinergic toxicity; it produced cholinergic adverse events and convulsions in animals anyway.

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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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