chloride channel: nootropics and compounds | sci-wiki

Alfaxalone

Alfaxalone (also spelled alphaxalone) is a synthetic neuroactive steroid of the pregnane class that produces general anesthesia by acting as a positive allosteric modulator (a molecule that amplifies a receptor's response to its own neurotransmitter) at the GABA-A receptor, the principal inhibitory ion channel of the central nervous system. First introduced in 1971 as the main active component of the intravenous anesthetics Althesin (human) and Saffan (veterinary), it was withdrawn from human use in the 1980s because the solubilizing vehicle Cremophor EL provoked anaphylactoid reactions, then reintroduced in a cyclodextrin formulation marketed for veterinary anesthesia as Alfaxan. Because it lacks classical hormonal activity yet retains rapid, non-cumulative central depressant effects, alfaxalone occupies a distinct pharmacological niche among intravenous anesthetics and now serves as a template for a new generation of water-soluble neurosteroid sedatives such as Phaxan.

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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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Anesthetic

Alphadolone

Alphadolone (alfadolone; clinically alphadolone acetate) is a synthetic neuroactive pregnane steroid (a laboratory-made steroid that acts on the nervous system) which potentiates the GABA-A receptor, the brain's principal fast inhibitory chloride channel, to produce sedation and anaesthesia. It is best known as the minor component of the intravenous anaesthetic Althesin (for humans) and Saffan (for animals), where it was combined with the more potent alfaxalone in a 3:1 ratio, added chiefly to improve the poor water solubility of alfaxalone while still contributing roughly half of that agent's anaesthetic potency in its own right. Both preparations were dissolved in the surfactant Cremophor EL, whose tendency to trigger histamine release and anaphylactoid reactions led to the withdrawal of Althesin from human use in 1984. Alphadolone later attracted independent research interest because, unlike alfaxalone, it produces spinally mediated analgesia without sedation when given by mouth or intraperitoneally, an effect thought to depend on an analgesic metabolite formed in the liver.

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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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Anesthetic

Org 20599

Org 20599 is a synthetic water-soluble aminosteroid general anaesthetic developed by Organon in the 1990s as a member of the 2-beta-morpholinyl pregnane class. Chemically it is (2beta,3alpha,5alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one, usually handled as its methanesulphonate (mesylate) salt, and it retains the 3-alpha-hydroxy, 5-alpha-reduced pregnane pharmacophore that defines the natural neurosteroid anaesthetics such as alphaxalone and allopregnanolone. Its principal action is positive allosteric modulation of the GABA-A receptor (the brain's main inhibitory chloride ion channel), with additional direct channel activation (GABA-mimetic agonism) at higher concentrations. It produced rapid-onset, short-duration anaesthesia in rodents but was never marketed; its close analogue Org 21465 reached Phase I human trials and caused excitatory involuntary movements in every volunteer, and the class was discontinued.

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Anesthetic

Renanolone

Renanolone (3alpha-hydroxy-5beta-pregnane-11,20-dione) is a synthetic pregnane steroid that was investigated as an intravenous general anaesthetic during the Glaxo steroid-anaesthetic program of the 1960s and 1970s. It is the 5beta-configured epimer of alphaxalone (alfaxalone), differing only in the stereochemistry of the A/B ring fusion, and it belongs to the same 3alpha-hydroxy-pregnane pharmacophore that defines neurosteroid modulators of the GABA-A receptor (the brain's principal inhibitory chloride ion channel). Like other steroid anaesthetics it produces sedation, hypnosis and anaesthesia by acting as a positive allosteric modulator of GABA-A receptors, although modern photoaffinity work shows it occupies the intersubunit neurosteroid pocket roughly twenty times more weakly than its 5alpha counterpart. Never marketed, it survives as a historical and mechanistic reference compound within the neurosteroid anaesthetic class.

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