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Gaboxadol

bupropion

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It's too bad this was cancelled (I think it got to Stage III)......I wonder if something with a similar mechanism of action will show up again?


Wikipedia said:
Gaboxadol was an experimental sleeping pill developed by Lundbeck and Merck. In March 2007, work was cancelled on the drug because of safety concerns. It acts on the GABA system, but in a very different way than benzodiazepines and 'z-drugs' (zolpidem, zaleplon, and zopiclone). Lundbeck states that gaboxadol also increases deep sleep (stage 4).


From Lundbeck site:

Gaboxadol is a direct-acting GABA-A receptor agonist with the chemical name 7-tetra hydroisoxazolo[5, 4-c]pyridin-3-ol (THIP).

Gaboxadol has a mode of action different from that of benzodiazepine receptor ligands. Thus, gaboxadol interacts directly with the GABA receptor site and activates GABA receptor populations, which are not modulated by benzodiazepines.

It has been suggested that the influence of direct-acting GABA-A agonists on NREM and REM sleep mimic the effect of a physiological increase in sleep need, suggesting GABA-A receptors may be involved in the homeostatic regulation of sleep. The effect of the direct acting GABA-A receptor agonist gaboxadol on sleep has been investigated in rats and humans. Gaboxadol increase the proportion of non-REM sleep in particular the slow wave sleep (deep sleep) without affecting the REM sleep. In details gaboxadol: increase the time spent in NREM sleep increase NREM sleep continuity enhance delta activity (deep sleep) within NREM sleep does not suppress REM sleep

Newer hypnotics like the indirect-acting positive GABA-A receptor benzodiazepine site modulators zolpidem, zopiclone and zaleplon, also increase the non-REM sleep, but in contrast to gaboxadol, reduce the slow wave sleep and REM sleep. The functional consequence of this altered sleep is impaired next-day performance and a sensation of fatigue, despite a full night’s sleep. In contrast, in human explorative studies, gaboxadol significantly improved the subjective sleep quality. These observations can be interpreted as if indirect acting GABA-A receptor modulators as the benzodiazepine like drugs produce sleep of a subjective poorer quality, whereas gaboxadol apparently enhances the quality of sleep.


In March, 2007, Merck and H. Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial.

About the efficacy thing - maybe if it improves sleep quality but isn't good enough for sleep induction it could be sold as a combo pill.


"Thus, gaboxadol interacts directly with the GABA receptor site and activates GABA receptor populations, which are not modulated by benzodiazepines."

Can someone explain what this means?



http://en.wikipedia.org/wiki/Gaboxadol
 

Ham-milton

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It potentiates GABA and it also acts as a direct agonist?

Not sure which subpopulations it's referring to- it's not a1 selective, but if it hits populations not hit by benzodiazepines, I'm guessing a4 and 6.
 

Poelster

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Do you for sure know this is cancelled? And if so why??

I never heard of it, did a quick search and all I can find is that it did entered phase III trails. Not that is cancalled. But this compount does sounds interesting..
 

mad_scientist

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I agree with what Hammilton said before about this compound, it looks an awful lot like muscimol, and I'm guessing it acts a similar way, just a slightly newer, "cleaned-up" version of amanita extract.

This is especially so seeing as one of the reasons they cited for dropping it in Phase III trials was that it caused hallucinations...I don't see why this is a reason for dropping a perfectly good sedative drug (look at zolpidem, zopiclone etc for instance) but maybe it was more hallucinogenic than those and not so amnestic, can't have people remembering that they were tripping out before they went to sleep!

Anyway gaboxadol does look interesting, wonder if its available as an RC...
 

Poelster

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Sorry, but I think saying Gaboxadol looks 'an awful lot' like Muscimol, is just a bit too much. Sure there are some simularities, but that's all.

I don't think this compount will have simmilair properties to Muscimol. I hope I'm wrong, because that would make this compount even more interesting.
 

Ham-milton

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There are a hell of a lot more than "some similarities" in between this molecule and muscimol.



These two molecules are extremely similar- the methylamine chain is locked into place, there's one less double bond in the pentagonal ring (in these depressants you find that pentagonal rings can be drastically altered and still retain very similar activity), and one less atom and a double bond from hydroxy to keto.

You really can't get much more similar without them being identical.
 

immaturepoop

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so oxidize the hydroxyl and reduce the imine to form an amide (or lactam?) and form the piperidine ring... not that different at all, pretty similar compounds. on muscimol wouldnt the amine be the only part of the chain that would rotate or or is there free rotation around the double bond? would forming the 6 membered heterocyclic amine be difficult? hmmmmm

edit: would muscimol exhibit keto-enol tautomerism?
 
Last edited:

MattPsy

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Gaboxadol looks essentuially like a conformationally restricted version of muscimol.
As far as I see it should exhibit tautomerism, yeah. This will have interesting effects on it's 1) penetration of the BBB and 2) it's renal (kidneys) elimination.
 

Reminisant B

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^Surprised it even made it to Phase III looking at the structure.

Isn't muscimol meant to be slightly neurotoxic? (not as bad as ibotenic acid but still not good?)
 

mad_scientist

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Interesting so they pulled it because of "psychiatric adverse events" when it was tested on "drug abusers" who took 2x-3x the maximum recommended dose. Sounds like this one could be a winner, especially as the safety profile other than the psychiatric effects is rather favourable.
 

MurphyClox

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immaturepoop said:
edit: would muscimol exhibit keto-enol tautomerism?
Yes, it does.

About the muscimol-similarity: Gaboxadol looks very much like a conformationally restricted muscimol-analogue. Period. Similarity can't be overlooked.
 

MurphyClox

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mad_scientist said:
Interesting so they pulled it because of "psychiatric adverse events" when it was tested on "drug abusers" who took 2x-3x the maximum recommended dose. Sounds like this one could be a winner, especially as the safety profile other than the psychiatric effects is rather favourable.
...and the fact that it even made it to Phase III shows us that this compound can't be that toxic. If they already decided to try it in humans, I'd give it a try, too.
 

Ham-milton

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It's commonly said that Muscimol is a hallucinogen, but that it doesn't produce real hallucinations or serotonergic hallucinations.

what the hell does it do? I've only tried it once and didn't get much out of it besides some sweating and a lot of salivation. Is salivation an issue with Gaboxadol?

Is muscimol more of a depressant or a psychedelic? Maybe I'd give it another shot if it was a depressant.
 

mad_scientist

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Muscimol is a GABAa agonist which actually binds to the same binding site on the receptor complex as GABA itself (as opposed to the barbiturates, benzodiazepines and nonbenzodiazepine drugs which all bind to seperate regulatory sites)

It does produce hallucinations at high doses but the hallucinogenic dose is also accompanied by quite strong sedation and amnesia so often people will fall asleep and/or not remember much of the experience if they take enough to actually get the hallucinogenic effect. The hallucinations are similar to those produced by other GABAergic drugs with hallucinogenic effects such as zolpidem.

The sweating is not from muscimol itself. Amanita mushrooms contain several different compounds, one of which muscarine is a peripherally acting muscarinic cholinergic agonist, so it produces the opposite peripheral effects to datura (i.e. you sweat and salivate profusely) but because it doesn't cross the blood brain barrier there are no CNS cholinergic effects, so the CNS effects of amanita mushrooms are from the muscimol.

Given the close structural similarity and the fact that gaboxadol also binds to the GABA site, its a fair bet that its effects are very similar to those of muscimol, but of course without the sweating and salivation as there will be no muscarine present in synthetic gaboxadol!
 

hamhurricane

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Gaboxadol report

25mg ingested after smaller doses suggested lack of acute toxicity/allergic effect.

Fast onset - within 10min on an empty(ish) stomach. Aesthetic enhancement and slightly improved visual acuity reminiscent of both zolpidem and certain cannabinoids. No outright visual distortions. No euphoria. Strong sedation and a very strong desire to lay down and go to sleep. Some mild proprioceptive funniness with eyes closed.

I keep myself awake waiting for some psychedelic ideation, despite the fact that this is a conformationally constrained muscimol analog, it is minimally psychedelic and differs in effect from muscimol greatly.

I fall asleep three full hours before I normally go to sleep and wake up three full hours earlier feeling extremely refreshed. Sleep was deep but not a black comatose sleep that one feels with cannabinoids, dreams were present but mild and friendly. No nightmares. It felt like the good natural sleep one gets after a day of exercise.

Significantly less euphoric and psychedelic than zolpidem - overall an excellent hypnotic with, as far as I can tell, minimal abuse potential.
 

hamhurricane

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Warning

A sample of Gaboxadol was analyzed with MS and found impure with the primary constituent being ibotenic acid. The sample contained no Gaboxadol. This is obviously very dangerous - anyone who has purchased this chemical should be extremely careful not to ingest it.
 

Astavats

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Thanks for the information Hamhurricane!

I can't help but ask, would it make sense for gaboxadol's degradation product to be ibotenic acid - the piperidine ring would break open and get oxygenated? Not implying this is the case above, just curious.
 
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