Any thoughts on α5IA (or other selective GABA-A-a5 antagonists)?

[CrazyEngineer]

So, I was doing Internet research on GABA-A receptors in the process of trying to explain the respective tolerance and OD risk profiles of zolpidem compared to benzos to somebody, and I stumbled on this gem. It's apparently a powerful inverse agonist of GABA-A subtype a5, while having weak partial agonist or inverse agonist activities at a1, a2, and a3-subtype receptors. Doing some more research, it appears that the a1 subtype mostly modulates sedation, a2 and a3 modulate anxiety, and that a5 affects memory and cognition. Benzodiazepines apparently activate all four receptors, causing sedation, anxiolysis, and also some degree of acute and cumulative impairment of memory and cognition. Zolpidem is reasonably selective for a1, so it knocks you out without really relieving anxiety or messing with your brain. By contrast, α5IA is an inverse agonist at a5 and a very weak partial agonist at a2; it would thus appear that α5IA would have a very weak anxiolytic effect while boosting memory and cognition.

I did some more research and found a few mouse and human studies of the stuff. They tested it in mice with Down's syndrome, and found that daily 5mg/kg injections of α5IA for two weeks repaired basically all of the deficits in several immediate early genes associated with memorization (and thus helped the mice achieve much faster times through a standard water maze). Some basic human trials have been done for safety and nootropic efficacy, and the results were interesting. Apparently α5IA did nothing or worse for elderly people (tests showed that a 4mg dose actually worsened performance on a paired-associate learning task for elderly patients), but it basically undid cognitive impairment due to drunkenness in young, healthy volunteers. As far as I can tell, the big risk is that one of its metabolites has a solubility in water of around 600 ng/mL, which is low enough that dramatically increased doses of α5IA caused some degree of kidney damage which precluded long-term dosing regimes in subjects. It's also apparently well-tolerated in people up to at least 6mg in the short term, and it might turn out to be a really useful drug.

I was wondering if anyone on here either has personal experience with the stuff, or has better medical knowledge of what happens when you shut down GABA-A-a5. It's currently only available for $28 per milligram, but I poked a friend of a friend who's going to grad school for chemistry about the feasibility of a synthesis for it and would like opinions on whether it's worth the trouble. This is also cross posted from OD becauseit seems like it would be more at home here.

 

[serotonin2A]

In what way does the water solubility of the metabolite cause it to produce kidney damage? Wouldn't the problem be that the metabolite is probably nephrotoxic, and so long-term exposure to the metabolite produces kidney damage?

 

[CrazyEngineer]

I'm unsure. The study said there were issues with the oxalate metabolite coming out of solution and crystallizing in the kidney, which then posed a risk of kidney damage. I've also heard that there are a couple of other studies out that weren't able to find any issues with kidney damage, so I'm unsure. Frankly, so far the kidney thing seems to be the only concrete drawback to this stuff, and if it turns out that the kidney thing either isn't reproducible or can be easily fixed by tweaking the molecule a bit then it would seem that this might be a nootropic home run.

 

[serotonin2A]

I'm unsure. The study said there were issues with the oxalate metabolite coming out of solution and crystallizing in the kidney, which then posed a risk of kidney damage. I've also heard that there are a couple of other studies out that weren't able to find any issues with kidney damage, so I'm unsure. Frankly, so far the kidney thing seems to be the only concrete drawback to this stuff, and if it turns out that the kidney thing either isn't reproducible or can be easily fixed by tweaking the molecule a bit then it would seem that this might be a nootropic home run.

If it is coming out of solution then that suggests the solubility is too low, not too high. The fact that there is some evidence of kidney damage should really make you think twice about taking this. It might make sense to use it to treat some illness, but as a general purpose nootropic? Your risking your health for uncertain, and possibly no, benefit.

I also have my doubts that any GABA-A allosteric modulator could be safe enough across the entire population to be used as a nootropic. I don't think this mechanism has been explored enough to really know if this is a good idea over the long term.

 

[CrazyEngineer]

I'm really curious about this, because the main issue I see with negative modulation of GABA-A is the chance of causing panic attacks or convulsions at high doses if your modulator turns out not to be selective enough for a5 over the other subtypes. This compound doesn't have that problem, since as far as I can tell it's actually a very weak partial agonist at a2 and I didn't find mentions of effects on any of the other GABA-A subtypes. The kidney thing is pretty concerning; I'm going to do a larger literature hunt to see if I can figure out where they got that information from and whether it applies to humans. I'm also wondering if any of the people here with a strong biochem background have suggestions about ways to modify the molecule that would preserve the important features (strong a5 inverse agonist, very weak partial agonism of a2, nothing else) without being metabolized into oxalates.

 

[Jakks]

Would be very interested to hear if you had any further developments on the a5IA....

 

[white55]

Aren't a5 and a1 the subunits that give the best bezos (strong hypnotics)?

 

[Solipsis]

a1 for sedation (Kopp et al), and a2 for anxiolyss (Rudolph et al)
a5 agonism apparently produces ataxia, problems with memory and anticonvulsant action (see QH-II-66), and what is called typical alcohol intoxication effects - though I think alcohol itself has multiple actions including on NMDAr.

So it seems a1 targeting ones would produce good sedatives / hypnotics, zolpidem being selective for it also shows this as effective hypnotic potential. a5 seems like action on it could add to recreational effects but also incapacitating side-effects. Your notion of 'best benzo' is also subjective - it depends on your aim.

I think actual action of the drugs is not 'on' these GABAa subunits but rather in between the above mentioned ones, and e.g. beta or gamma subunits next to it which also make up the receptor. What these are is perhaps of less importance? Or more resulting in how each person reacts since they may have different expressions or mutations / polymorphisms of the receptors?

Novelty is nice but I would really always wait until there is at least some data in humans before you go screwing with your cognition and potentially anxiety even if in animals we don't see significant adverse effects on that due to antagonism at subunits other that a5. Let alone the toxicology... I've been in trials with cannabinoids many years ago and there was an incident that was fortunately not life or health threatening and now the braindead etc people in France? Pretty shocking.

Just try common nootropics, that's enough experimenting as it is considering the risks... anyway it's tough arguing with obsession, not necessarily saying that's you (it has been me for years generally - but I grew milder with the experimenting), though if you wanna push this, yeah that would sound about right.

Serotonin2A ^ is very good to take advice from

And fwiw it does not look like an easy synthesis, especially not to have someone do casually..

 

[clubcard]

pure a5 is just like alcohol. Pyeyzolam