Gaboxadol

Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolopyridin-3-ol and by its former developmental code names Lu-2-030, MK-0928, and OV101, is a GABA_A receptor agonist related to muscimol which was investigated for the treatment of insomnia and other conditions like Angelman syndrome but was never marketed. At lower doses, the drug has sedative and hypnotic effects, and at higher doses, it produces hallucinogenic effects. It is taken orally.
The drug acts as a potent and selective partial agonist of the GABA_A receptor, the major signaling receptor of the inhibitory endogenous neurotransmitter γ-aminobutyric acid. However, it acts as a preferential supra-maximal agonist at extrasynaptic δ subunit-containing GABA_A receptors. In contrast to GABA_A receptor positive allosteric modulators like benzodiazepines and Z drugs, gaboxadol is an orthosteric agonist of the GABA_A receptor, acting on the same site as GABA rather than at an allosteric regulatory site. As a result, gaboxadol has differing effects from benzodiazepines and related drugs. Gaboxadol is a conformationally constrained synthetic analogue of GABA and of muscimol, an alkaloid and hallucinogen found in Amanita muscaria mushrooms. It has greatly improved drug-like properties compared to these compounds.
Gaboxadol was first described by Povl Krogsgaard-Larsen and colleagues in 1977. It was assessed in clinical studies for various uses in the 1980s, but was not found to be useful. In the 1990s and 2000s, gaboxadol was repurposed for treatment of insomnia and completed phase 3 clinical trials for this indication. However, development was discontinued for safety and effectiveness reasons in 2007. Subsequently, gaboxadol was repurposed again for treatment of Angelman syndrome and fragile X syndrome, but was later abandoned completely.

Use and effects

Gaboxadol produces sedative and hypnotic effects at lower doses and hallucinogenic effects at higher doses. It has also been reported to produce mood elevation and sometimes euphoria.

Hypnotic effects

Gaboxadol has been assessed in clinical studies at doses ranging from 10 to 160mg. It was studied in clinical trials for treatment of insomnia specifically at doses of 5 to 20mg. The drug's effects at a dose of 10mg were anecdotally described by Povl Krogsgaard-Larsen as similar to having drunk two or three beers. It was found to be limitedly effective for improving sleep at doses of 5 and 10mg, but was more effective at doses of 15 to 20mg. Higher doses for insomnia were precluded by a narrow therapeutic index and high rates of psychiatric adverse effects at such doses.
Gaboxadol has been found to decrease sleep onset latency, increase sleep duration, increase slow wave sleep and slow wave activity, preserve sleep architecture, not affect REM sleep, and improve subjective sleep quality and daytime functioning. The drug was found to allow people to fall asleep and stay asleep whilst exposed to continuous recorded stream of road traffic noise, a model of transient insomnia. Gaboxadol's hypnotic effects have been found to be stronger in women than in men. On the other hand, SWS decreases with age, especially in men, and gaboxadol was found to substantially compensate for the reduction in SWS in elderly men. The drug was also studied in experimental sleep restriction and was found to increase SWS and improve daytime functioning, for instance symptoms of sleepiness and fatigue, despite equal total sleep durations.
There was no tolerance to the hypnotic effects of gaboxadol after 5days of repeated administration in animals. Similarly, it maintained effectiveness in short-term clinical studies in humans. However, gaboxadol was subsequently found to be initially effective in improving sleep in insomnia but to not maintain its benefits after 1month. In addition, gaboxadol showed mixed effectiveness at the assessed doses of 10 to 15mg in two large 3-month clinical trials for insomnia.
The effects of gaboxadol on sleep differ from those of widely used GABA_A receptor positive allosteric modulators like benzodiazepines and Z drugs, which have been found to disrupt rather than enhance SWS and SWA despite improving sleep onset and duration. In addition, unlike such agents, gaboxadol caused no rebound insomnia on discontinuation and produced no next-day residual symptoms. While dissimilar from GABA_A receptor positive allosteric modulators, the effects of gaboxadol on sleep are similar to those of the related GABA_A receptor agonist muscimol and of the GABA reuptake inhibitor tiagabine.
Although gaboxadol was found to be effective in the treatment of insomnia and uniquely able to improve SWS, it was found to have less robust effects on traditional hypnotic effectiveness measures like sleep onset and duration at the evaluated doses compared to zolpidem. In addition, it was more effective for improving sleep maintenance than for improving sleep onset.
Gaboxadol was developed for the treatment of insomnia, in which disruption of SWS is not the main feature. The effects of gaboxadol in people with sleeping problems specifically involving impaired SWS have largely not been studied and are unknown.

Hallucinogenic effects

Gaboxadol was assessed at supratherapeutic doses of 30 to 45mg and compared to the Z drug zolpidem in drug users during its development for treatment of insomnia. At these doses, gaboxadol produced euphoria and hallucinogenic effects such as dissociation, perceptual changes, and hallucinations. The rates of such psychiatric adverse effects were 15% with placebo, 38% with 15mg, 72% with 30mg, and 88% with 45mg gaboxadol. It showed less euphoria and misuse potential, more negative and dissociative effects, and fewer sedative effects than zolpidem in these individuals. At a dose of 60mg twice daily in an early study, gaboxadol was described as producing effects including dizziness, vomiting, somnolence, and strong sedation. High doses of gaboxadol have also been reported to produce delirium, amnesia, and loss of consciousness.
According to journalist and scientist Hamilton Morris, the drug can produce strong hallucinogenic effects at high doses similarly to muscimol, with hallucinogenic effects starting at around doses of 30 or 40mg and powerful hallucinogenic effects occurring at a dose of about 65mg of the zwitterion. Morris has described hallucinogenic effects he experienced with gaboxadol as follows:
He has also reported other qualitative accounts of the hallucinogenic effects of gaboxadol. Morris has stated that gaboxadol is every bit as powerful as a hallucinogen as serotonergic psychedelics like ayahuasca, but is qualitatively completely different.

Side effects

s of gaboxadol include dizziness, sedation, somnolence, headache, nausea, vomiting, and tachycardia, among others. It has also been reported to produce giddiness, depersonalization, impaired concentration, and bradycardia. In clinical studies for insomnia, gaboxadol has been found to be generally well-tolerated for up to 12months. At high doses, it can produce hallucinogenic effects and delirium.

Interactions

Gaboxadol is metabolized exclusively via glucuronidation and is not appreciated metabolized by cytochrome P450 enzymes, and hence would not be expected to interact with cytochrome P450 inhibitors or inducers.
In contrast to the case of γ-aminobutyric acid and muscimol, the binding of gaboxadol to the GABA_A receptor does not appear to be stimulated by the benzodiazepine and GABA_A receptor positive allosteric modulator diazepam in vitro. In addition, gaboxadol did not show synergistic effects in combination with alcohol or benzodiazepines in vitro or in vivo in animals.

Pharmacology

Pharmacodynamics

Gaboxadol acts as a potent and selective GABA_A receptor partial agonist. In contrast to GABA_A receptor positive allosteric modulators like benzodiazepines, Z drugs, barbiturates, and alcohol, gaboxadol is an agonist of the orthosteric site of the GABA_A receptor and the same site that the neurotransmitter γ-aminobutyric acid binds to and activates. Whereas the related GABA_A receptor agonist muscimol is a highly potent partial agonist of the GABA_A-ρ receptor, gaboxadol is a moderately potent antagonist of this receptor. Unlike muscimol, it is not also a GABA reuptake inhibitor to any extent, and it does not inhibit the enzyme GABA transaminase.
The drug shows functional selectivity at the GABA_A receptor relative to GABA itself, activating GABA_A receptors of different α subunit compositions with varying efficacies. Its values at GABA_A receptors were approximately 71% at α₁ subunit-containing receptors, 98% at α₂ subunit-containing receptors, 54% at α₃ subunit-containing receptors, 40% at α₄ subunit-containing receptors, 99% at α₅ subunit-containing receptors, and 96% at α₆ subunit-containing receptors. Moreover, gaboxadol has been found to act as a supra-maximal agonist at α₄β₃δ subunit-containing GABA_A receptors, low-potency agonist at α₁β₃γ₂ subunit-containing receptors, and partial agonist at α₄β₃γ subunit-containing receptors. Its affinity for extrasynaptic α₄β₃δ subunit-containing GABA_A receptors is 10-fold greater than for other subtypes. Gaboxadol has a unique affinity for extrasynaptic α₄β₃δ subunit-containing GABA_A receptors, which mediate tonic inhibition and are typically activated by ambient, low levels of GABA in the extrasynaptic space. The supra-maximal efficacy of gabaxadol at α₄β₃δ subunit-containing GABA_A receptors has been attributed to an increase in the duration and frequency of channel openings relative to GABA. Mice with the GABA_A receptor δ subunit knocked out are unresponsive to the hypnotic effects of gaboxadol. Because of its preferential agonism of extrasynaptic GABA_A receptors, gaboxadol has been referred to as a "selective extrasynaptic GABA_A agonist" or "SEGA". In contrast to gaboxadol, benzodiazepines and nonbenzodiazepines do not activate δ subunit-containing GABA_A receptors. On the other hand, alcohol is known to selectively potentiate δ subunit-containing extrasynaptic GABA_A receptors analogously to gaboxadol. In addition, neurosteroids and propofol act on extrasynaptic δ subunit-containing GABA_A receptors.
Gaboxadol shows 25- to 40-fold lower potency as a GABA_A receptor agonist than muscimol in in vitro studies. Compared to muscimol, gaboxadol binds less potently to α₄β₃δ subunit-containing GABA_A receptors, but is capable of evoking a greater maximum response. Although gaboxadol is far less potent than muscimol in vitro, it is only about 3times less potency than muscimol in rodents in vivo. This is attributed mainly to gaboxadol's much greater ability to cross the blood–brain barrier than muscimol. However, it appears to be due to gaboxadol levels being several-fold higher than levels of muscimol with systemic administration of the same doses as well. Gaboxadol is also more selective than muscimol and has been said by Povl Krogsgaard-Larsen to be much less toxic in comparison.
In animals, gaboxadol has been found to produce sedation, hypnotic effects, motor impairment, muscle relaxation, hypolocomotion, anxiolytic-like effects, antidepressant-like effects, analgesic effects, and anticonvulsant effects. In rodent drug discrimination studies, gaboxadol has been found to fully generalize with muscimol. However, gaboxadol, GABA_A receptor positive allosteric modulators like benzodiazepines and Z drugs, and the GABA reuptake inhibitor tiagabine all do not generalize between each other, suggesting that their interoceptive effects are different. Similarly, gaboxadol did not generalize with the neurosteroid pregnanolone. On the other hand, gaboxadol has shown partial generalization with the barbiturate pentobarbital. Gaboxadol does not produce self-administration or conditioned place preference in rodents or baboons, suggesting that it lacks rewarding or reinforcing effects and has low addictive potential. This is in contrast to benzodiazepines like diazepam.