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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.
- Potent positive allosteric modulator of the GABA-A receptor in preclinical assays
- Produced rapid-onset, short-duration anaesthesia (loss of righting reflex) in mice
- Anaesthetic potency comparable to alphaxalone and greater than propofol, thiopentone or pentobarbitone in rodent assays
- Water-soluble as a mesylate salt, formulatable in aqueous solution without the Cremophor EL surfactant linked to allergic reactions
- A clean, well-characterised experimental tool for probing the transmembrane neurosteroid site on GABA-A receptors
- Class-associated excitatory phenomena and involuntary movements (documented in humans for the sibling compound Org 21465)
- Venous pain at the injection site reported for the aminosteroid class in human trials
- Expected general-anaesthetic risks of respiratory and cardiovascular depression for any intravenous agent of this type
Overview
A niche, historical Organon water-soluble aminosteroid neurosteroid anaesthetic; a potent GABA-A positive modulator whose class-wide excitatory liability ended its clinical development.
- The whole point of the 2-beta-morpholinyl group was water solubility; the basic nitrogen lets the steroid be dissolved as a mesylate salt in plain aqueous solution, sidestepping the Cremophor EL vehicle whose allergic reactions had gotten the earlier steroid anaesthetic Althesin withdrawn.
- Org 20599 is not a pure allosteric modulator; at concentrations above those needed to potentiate GABA it directly opens the chloride channel on its own (a GABA-mimetic action), and this dual behaviour is thought to help explain the excitatory movements seen with the class.
- Its close analogue Org 21465 reached Phase I trials in human volunteers and produced involuntary excitatory movements in every single subject, which is what ended the program.
- Small changes matter within one chemical series: in a spinal antinociception screen Org 20599 produced no analgesia at all, whereas sibling aminosteroids Org 20380 and Org 20549 from the same family did produce GABA-A-mediated, bicuculline-sensitive spinal analgesia.
Mechanism
Org 20599 acts principally as a positive modulator (a compound that binds a site distinct from the neurotransmitter site and increases receptor function) of the -A receptor, the pentameric -gated chloride channel that mediates most fast inhibitory neurotransmission in the mammalian brain. The molecule preserves the two structural features known to be obligatory for neurosteroid activity at this receptor: a 3-alpha-hydroxyl group and a 5-alpha (A/B trans) ring fusion on a pregnan-20-one backbone, the same configuration found in the endogenous neurosteroid allopregnanolone (5-alpha-pregnan-3-alpha-ol-20-one) and in the clinical steroid alphaxalone. Onto this scaffold Organon appended a 2-beta-morpholinyl group; the basic (protonatable) nitrogen of that morpholine ring is what makes the otherwise steroid ionisable and therefore water-soluble as a methanesulphonate salt, and a 21-chloro substituent completes the side chain.
At the receptor, Org 20599 binds the transmembrane neurosteroid site (in later cryo-electron-microscopy and mutagenesis work localised to a pocket formed by the M1 and M4 helices at the interface of the alpha and beta subunits) rather than the benzodiazepine or barbiturate sites. Binding there potentiates -evoked currents by increasing channel open probability and prolonging channel open times, producing a concentration-dependent, reversible increase in peak current amplitude at human recombinant alpha1-beta2-gamma2L receptors expressed in Xenopus oocytes and at native receptors on bovine adrenal chromaffin cells and cultured rat hippocampal neurones. Consistent with this, Org 20599 allosterically displaces the cage convulsant [35S]-TBPS (t-butylbicyclophosphorothionate) from the picrotoxin/channel site of rat brain membranes, with a potency intermediate between allopregnanolone and alphaxalone and greater than propofol, thiopentone or pentobarbitone. A defining and pharmacologically important second action is that, at concentrations above those needed for potentiation, Org 20599 directly gates the channel in the absence of GABA (a GABA-mimetic or direct- effect); the magnitude of this direct action varies markedly across the anaesthetic-steroid series and is thought to contribute to the excitatory phenomena seen with the class.
Org 20599 is a purely synthetic analogue and has no endogenous biosynthetic pathway; unlike the true neurosteroids it is not produced from cholesterol or progesterone by 5-alpha-reductase and 3-alpha-hydroxysteroid dehydrogenase. Its detailed human metabolism and active metabolites were never fully characterised in the published literature, the program having been terminated at an early stage; the morpholine nitrogen and the 21-chloromethyl ketone represent the likely sites of biotransformation.
receptor fingerprint
-A receptor (alpha1-beta2-gamma2L)Positive allosteric potentiation of GABA-evoked chloride current
-A receptor (neurosteroid site)Positive allosteric modulator
TBPS / picrotoxin convulsant siteAllosteric displacement of [35S]-TBPS binding
Glycine receptorWeak modulation relative to GABA-A (steroid class)
Barbiturate/TBOB site (-A)Allosteric interaction with GABA
-A receptor (direct channel gating)Direct GABA-mimetic agonism at higher concentrations
Safetyrisks and cautions, not medical advice
No safety data exist for Org 20599 in humans, and the compound has no legitimate consumer, supplement or therapeutic use; it is a discontinued investigational anaesthetic of purely historical and research interest. What is known about the wider 2-beta-morpholinyl aminosteroid class comes largely from Phase I studies of the sibling agent Org 21465, in which intravenous administration produced anaesthesia but also venous pain at the injection site and excitatory involuntary movements in every subject tested.
These excitatory phenomena, plausibly linked to the direct GABA-mimetic channel activation shown for Org 20599, are the central safety concern for the series and were the proximate reason the clinical program was abandoned. As an intravenous general anaesthetic, any such compound would carry the usual class risks of respiratory and cardiovascular depression and would only ever be appropriate under full anaesthetic monitoring; none of that is relevant today because the molecule is not in use.
History
Org 20599 emerged from an Organon medicinal-chemistry program in the early-to-mid 1990s aimed at solving a specific problem: the neurosteroid anaesthetic alphaxalone (the active component of Althesin and of the veterinary product Saffan) was clinically attractive but almost insoluble in water, so it had to be formulated in the surfactant Cremophor EL, which was implicated in anaphylactoid and histamine-release reactions and led to Althesin's withdrawal for human use. To make an inherently water-soluble steroid, chemists attached an ionisable 2-beta-morpholinyl group to the 3-alpha-hydroxy-5-alpha-pregnane pharmacophore, allowing formulation as a simple aqueous mesylate salt without any surfactant.
Org 20599 became the lead pharmacological characterisation compound; Hill-Venning and colleagues reported its anaesthetic and GABA-A profile in Neuropharmacology in 1996, and Anderson and coworkers described the medicinal chemistry of the morpholinyl-steroid series in the Journal of Medicinal Chemistry in 1997. A closely related analogue, Org 21465, was advanced into Phase I human volunteer studies (Sneyd and colleagues, 1997). When those trials revealed excitatory involuntary movements in all participants together with slow biophase equilibration and injection-site pain, the water-soluble aminosteroid anaesthetic effort was discontinued, and the compounds passed into the historical and mechanistic literature.
Reputation
Within academic pharmacology Org 20599 is regarded as a useful and potent experimental probe of GABA-A receptor modulation, and it appears in the foundational neurosteroid literature from the Dundee group (Lambert, Peters, Belelli and colleagues) who characterised it. In clinical and commercial terms it is a historical footnote: it was never approved, is not available for any human or supplement use, and is remembered chiefly as part of the failed effort to produce a water-soluble successor to Althesin. The class is often cited as a cautionary example of how GABA-A-active steroids that also directly gate the channel can carry an excitatory (rather than purely sedative) liability.
Subjective profileweighing the evidence above
A discontinued investigational anaesthetic with no human safety record and no use outside history. Its sibling compound caused injection-site pain and involuntary movements in every subject dosed, which is the class problem, and any intravenous agent of this type risks respiratory depression.
Resources
This entry is here for reference.
Research
- 1995first citedNeurosteroids and GABAA receptor function.
- 1997most active year4 papers
- 2024most recentNeurosteroids and their potential as a safer class of general anesthetics.
- 1.The anaesthetic action and modulation of GABAA receptor activity by the novel water-soluble aminosteroid Org 20599.
- 2.Anesthetic activity of novel water-soluble 2 beta-morpholinyl steroids and their modulatory effects at GABAA receptors.
- 3.Administration to humans of ORG 21465, a water soluble steroid i.v. anaesthetic agent.
- 4.Computer-controlled infusion of ORG 21465, a water soluble steroid i.v. anaesthetic agent, into human volunteers.
- 5.ORG 21465, a new water-soluble steroid hypnotic: more of the same or something different?
- 6.Antinociceptive properties of neurosteroids I. Spinally-mediated antinociceptive effects of water-soluble aminosteroids.
- 7.Antinociceptive properties of neurosteroids II. Experiments with Saffan and its components alphaxalone and alphadolone to reveal separation of anaesthetic and antinociceptive effects and the involvement of spinal cord GABA(A) receptors.
- 8.Pharmacological modulation of GABA(A) receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus.
- 9.Neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA(A) receptor in vivo.
- 10.The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors.
- 11.A molecular model for the synergic interaction between gamma-aminobutyric acid and general anaesthetics.
- 12.Neurosteroids and GABAA receptor function.
21 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
What is Org 20599?
It is a synthetic, water-soluble aminosteroid general anaesthetic made by Organon in the 1990s. It is a 2-beta-morpholinyl analogue of natural neurosteroid anaesthetics such as alphaxalone and works mainly by boosting the GABA-A receptor, the brain's principal inhibitory chloride channel.
How does Org 20599 work in the brain?
It binds the transmembrane neurosteroid site on the GABA-A receptor and acts as a positive allosteric modulator, prolonging channel opening and increasing GABA-evoked inhibitory current. At higher concentrations it can also open the channel directly on its own, a GABA-mimetic action shared with other anaesthetic steroids.
Was Org 20599 ever used in people?
No. Org 20599 itself stayed a preclinical and mechanistic research compound. Its close relative Org 21465 was given to human volunteers in Phase I studies, but excitatory involuntary movements in every subject led to the class being discontinued.
Why did Organon want a water-soluble steroid anaesthetic?
The earlier steroid anaesthetic alphaxalone had to be dissolved in the surfactant Cremophor EL because it is nearly insoluble in water, and that vehicle caused serious allergic reactions. Adding an ionisable morpholine ring at the 2-beta position made Org 20599 soluble as a simple aqueous salt without any surfactant.
Is Org 20599 available as a supplement or nootropic?
No. It is a discontinued investigational intravenous anaesthetic with no approved use, no consumer availability, and no established human safety data. It is relevant only as a piece of neurosteroid pharmacology history.
Limitations of the evidence
- Direct GABA-mimetic channel activation at higher concentrations, a plausible driver of the excitatory side effects
- Never approved; human safety profile of Org 20599 itself was never established
Adverse effects
- Class-associated excitatory phenomena and involuntary movements (documented in humans for the sibling compound Org 21465)
- Venous pain at the injection site reported for the aminosteroid class in human trials
- Expected general-anaesthetic risks of respiratory and cardiovascular depression for any intravenous agent of this type