Yeah, I am considering purchasing ISRB "for research". Some people I love suffer with chronic inflammation due to various autoimmune diseases. I know plenty of amateur body builders buy chemicals "for research" but use them as supplements. They keep tabular and video artifacts like most body builders do, so I wonder to what degree the activities are illegal?
The problem with ISRIB is that it isn't water soluble. I'm not convinced that people who take it (usually subcutaneous injection or snorting it) aren't just experiencing placebo. I don't know of any way of actually getting the molecule to your body's cells in a consistent manner.
The study dissolved it in DMSO, then that in polysorbate 80, then that in polyethylene glycol. Then injected that intraperitoneally. That seems doable.
DMSO is soluble in both polar and non polar solvents. I assume the insolubility in water is precisely what they used it to solve.
Im any case, their delivery mechanism worked in mice, so it would work in people. The part that might not carry over to people is the effect once in the cell.
Intraperitoneal injection isn't really done in humans, the closest equivalent would be subcutaneous or maybe intramuscular injection. I don't know about the safety of injecting DMSO into humans but it's probably not too bad since it seems perfectly safe when used for transdermal drug delivery. The bigger problem is that you're injecting a water-insoluble compound mixed in a small amount of solvent into what is essentially a big bag of water. Once that DMSO/PEG/whatever is injected, it will just mix with the water in your body, so the ISRIB will just precipitate out of solution since it is now surrounded by 99% water molecules. So it will never get distributed to all your organs, which is the goal.
Also laboratory mice are not necessarily comparable to the diversity in genetics of even wild mice (or the genetic diversity of the human population if we want to extrapolate).
I add this warning because I'm seeing a lot of younger software engineers try out custom peptides to boost their iq, memory, and work ability.
Eh, I say let 'em. People need to stop pretending aging isn't a tragedy just because it's our natural state. We should be as bold with treatments for it as we are with treatments for other fatal diseases.
Me and every one of my friends have seen this horse named Hans, very clever, that could understand everything its trainer said. He could do arithmetic too! I don’t understand why big psychology won’t take our data seriously and finally accept that horses are capable of long division.
>People need to stop pretending aging isn't a tragedy just because it's our natural state. We should be as bold with treatments for it as we are with treatments for other fatal diseases.
We don't encourage people to experiment with self medicating themselves for cancer and multiple sclerosis, because it's dangerous and most people have no idea what they're doing. It's pretty much the same thing here. I know it'll happen either way, but I wouldn't recommend it to the average person.
As usual, I fear comments will focus on the "in mice" part, forgetting that for most base circuits (ex: brain, nerves ...) and physiology (scarring, aging, inflammation ...) they are extremely close.
Also, other "cognitive enhancers" have usually found effects in both rodents and primates.
And then someone will come in and tell you that most things tried in mice don't work out in humans, and we will issue a collective shrug as we don't know what to believe.
What doesn't work in mice is typically for mouse-models of diseases: we try to replicate a disease based on what we think causes it, then try to cure it.
That's typical for cancer, Alzheimer etc. No wonder the things tried in the toy problem don't work out when faced with the real problem!
The problem isn't so much the mice being so different, but the disease itself being very different from the toy problem.
The nice thing is that you don't need to decide what to believe. You just keep doing experiments and, if well designed, they'll tell you what's true anyway. These animal model experiments are not intended to prove applicability to humans, they're intended to prove that you can take the next (tiny) step along the (extremely long) road to human applicability.
Of course translational research is necessary with such results.
Explicit goal of developing cognitive enhancing therapies set by NIH would greatly help motivate such research.
That would be pretty good, apply the best cancer prevention, longevity producing, cancer protecting treatments available to 100 mice, compared to the diet of a typical American in 100 other mice (not very ethical I know) and see what happens.
I for one do not understand that we do not share our discoveries with nature. After all these animal experimentations we have big debt. It would only be decent to give something back.
I think we already made stronger and smarter(with human brain cells) mice. What if make every wild animal smarter in the same fashion?
Can we also improve photosynthesis?
Because we compete for resources with animals and there is no inhibition to prevent them from deploying additional intelligence to hurt, hunt, or starve humans.
Just because something is dismissed today as a promising candidate doesn't prove it'll never be used for something else in the far future. Many toxic drugs later found use in chemotherapy for cancer; it was suddenly good they were toxic
For what it's worth, just as an amateur chemist staring hard at the molecule, it looks like the ligand (the outer bit that plugs into receptor binding sites) consists of a monochlorinated benzene ring. Which would likely put this in the same drug class as https://en.wikipedia.org/wiki/Bromantane, whose ligand is a monobrominated benzene ring — and which is also a "cognitive enhancer" nootropic with a thusfar not well understood mechanism-of-action.
The naive assumption some people make is that bromantane (and so probably also ISRIB) would have an at least partially similar MoA to amphetamine, given that amphetamine has a plain old benzene ring hanging off of one end of it; but IIRC that is incorrect, as, in amphetamine, the benzene is not the ligand — rather, the amide group on the other end is.
Computational chemist here, working at the moment on small molecule ligands in the context of drug discovery.
The small molecule itself is the ligand. There is interaction of the ligand with the binding site amino acids via hydrogen bonds to several locations on the ligand.
Have a look at the RCSB PDB entry for 6EZO - ISRIB bound to eIF2B (the 3D view is https://www.rcsb.org/3d-view/6EZO), turn on Dynamic Bonds and click on the ligand.
While this static shot does not reveal all the interactions (such as those that are longer-range, cation-pi, water-mediated, and so on) that one would see in a molecular dynamics simulation or by docking, it's very useful.
Finally, when benzene is attached to something, it's a phenyl group; amphetamine is the ligand; and the functional group is amine, not amide.
Is there a term for a part of a molecule that takes part in “medium range” interactions — making the molecule electrostatically attracted toward/repulsed away from specific macromolecule binding sites, like is happening with the hydrogen bonds here — but which don’t then take part in any kind of redox or polymerization reaction once the molecule reaches close enough for such to take place? Because that’s what I meant here by trying to distinguish which part of these molecules is the ligand: which part is getting directly chemically reacted with / away (triggering the state change in the receptor), vs. the part being interacted with only indirectly in the sense of “a key that fits into a molecular lock vs. a key that doesn’t”.
What I’ve been told is that the phenyl group in amphetamine isn’t reacted with / reacted away by a DA receptor binding site, but rather just gives it its binding affinity by being the right shape to fit into (and the right charge + mass to be attracted by) DAR and DATR binding sites without the indirect forces of the “walls” of these receptors repulsing it.
Under this logic (if it’s sound, which you seem to be saying it’s not), a brominated phenyl group would really just be a bromide ion in direct reaction terms — it’d theoretically attach to any chloride channel. The phenyl group it’s riding on, would — along with the rest of the molecule — serve to ensure that the bromide ion only gets to come into contact with chloride channels inside receptors that allow a phenyl group inside them, rather than repulsing phenyl groups, or not being the right shape to accept phenyl groups.
(This logic — again, if sound — would also suggest that chlorhexidine would have a similar nootropic effect if it could cross the blood-brain barrier.)
Mid-range is hard to define, really. There are weaker electrostatic effects, and the pi-stacking and/or cation-pi effects are over longer ranges than h-bonds typically are.
The whole molecule is the ligand: when you state you are "trying to distinguish which part of these molecules is the ligand," I again state that the whole thing is the ligand.
The parts that bind to moieties in the active site vs. the parts that might not do so directly are equally important. In your example with amphetamine, I can assure you that the electron-rich conjugated aromatic ring is very important, even if you don't see hydrogen bonding. Remember, we are talking about overall steric and electrostatics here.
If you want a bromide ion, just use a bromide salt: that directly gives you Br^{-1}. Swapping a single atom in a molecule can drastically change PK/PD properties, so caveat emptor.
As for chlorhexidine, it's an antibacterial on the upper limit of breaking at least one of Lipinski's RO5, although that's not a showstopper. There is no guarantee at all that it would behave like a similar compound.
If you are looking for a cognitive enhancer then caffeine and modafinil / provigil have been proven to enhance focus. I believe that latter of those is used extensively by fighter pilots and other military to stay alert; and the former is used by pretty much everybody for the same purpose.
I know drink a cup of coffee is probably not the answer a lot of the nootropic heads are looking for; but I don’t think there are any silver bullets here.
This is one of the reasons I switched to fine mesh coffee filter (metal) a while back, instead of paper filters, hoping to get more of the goodness of coffee in me. Although it does let cafestol through as well, but that doesn't seem like much of a big deal if you don't have any cholesterol issues.
I've taken adrafinil off and on over the years and it doesn't do much of anything for me. Not sure if I'm expecting too much or what's going on with that.
skin rash or hives, blisters or peeling, mouth sores, trouble breathing or swallowing, fever, swelling in your legs, dark urine, yellowing of your skin or eyes, or swelling in your face!? And there's more:
https://www.drugs.com/provigil.html
78 comments
[ 3.2 ms ] story [ 161 ms ] threadOdds are the same basic mechanism is activated by many other things, including some inflammation process.
Try NAC, CBD, PEA (Palmitoylethanolamide; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406356/), DHA/EPA (fish oil) and other things to reduce brain inflammation.
But trans-ISRIB looks exactly on point in its particular mechanism.
You can already import it in bulk from manufacturers like nutrabiotechchem.com.
Also Are you currently on any discord servers ?
https://www.reuters.com/business/healthcare-pharmaceuticals/...
I add this warning because I'm seeing a lot of younger software engineers try out custom peptides to boost their iq, memory, and work ability.
Eh, I say let 'em. People need to stop pretending aging isn't a tragedy just because it's our natural state. We should be as bold with treatments for it as we are with treatments for other fatal diseases.
95% made a bad situation much worse. Memantine Had a moderate boost.
Went on a Blood thinner and everything resolved.
We don't encourage people to experiment with self medicating themselves for cancer and multiple sclerosis, because it's dangerous and most people have no idea what they're doing. It's pretty much the same thing here. I know it'll happen either way, but I wouldn't recommend it to the average person.
Hence "let them", not "encourage them". The average person doesn't have the slightest idea what a "custom peptide" is.
Also, other "cognitive enhancers" have usually found effects in both rodents and primates.
>Learned Sage Points Out That Powerball Not As Much After Taxes https://www.theonion.com/learned-sage-points-out-that-powerb...
Whether it's mice or powerball, the lowest hanging fruit is the Learned Sage comment, noting that things aren't quite as they seem.
That's typical for cancer, Alzheimer etc. No wonder the things tried in the toy problem don't work out when faced with the real problem!
The problem isn't so much the mice being so different, but the disease itself being very different from the toy problem.
https://news.ycombinator.com/newsguidelines.html
The naive assumption some people make is that bromantane (and so probably also ISRIB) would have an at least partially similar MoA to amphetamine, given that amphetamine has a plain old benzene ring hanging off of one end of it; but IIRC that is incorrect, as, in amphetamine, the benzene is not the ligand — rather, the amide group on the other end is.
The small molecule itself is the ligand. There is interaction of the ligand with the binding site amino acids via hydrogen bonds to several locations on the ligand.
Have a look at the RCSB PDB entry for 6EZO - ISRIB bound to eIF2B (the 3D view is https://www.rcsb.org/3d-view/6EZO), turn on Dynamic Bonds and click on the ligand.
While this static shot does not reveal all the interactions (such as those that are longer-range, cation-pi, water-mediated, and so on) that one would see in a molecular dynamics simulation or by docking, it's very useful.
Finally, when benzene is attached to something, it's a phenyl group; amphetamine is the ligand; and the functional group is amine, not amide.
Is there a term for a part of a molecule that takes part in “medium range” interactions — making the molecule electrostatically attracted toward/repulsed away from specific macromolecule binding sites, like is happening with the hydrogen bonds here — but which don’t then take part in any kind of redox or polymerization reaction once the molecule reaches close enough for such to take place? Because that’s what I meant here by trying to distinguish which part of these molecules is the ligand: which part is getting directly chemically reacted with / away (triggering the state change in the receptor), vs. the part being interacted with only indirectly in the sense of “a key that fits into a molecular lock vs. a key that doesn’t”.
What I’ve been told is that the phenyl group in amphetamine isn’t reacted with / reacted away by a DA receptor binding site, but rather just gives it its binding affinity by being the right shape to fit into (and the right charge + mass to be attracted by) DAR and DATR binding sites without the indirect forces of the “walls” of these receptors repulsing it.
Under this logic (if it’s sound, which you seem to be saying it’s not), a brominated phenyl group would really just be a bromide ion in direct reaction terms — it’d theoretically attach to any chloride channel. The phenyl group it’s riding on, would — along with the rest of the molecule — serve to ensure that the bromide ion only gets to come into contact with chloride channels inside receptors that allow a phenyl group inside them, rather than repulsing phenyl groups, or not being the right shape to accept phenyl groups.
(This logic — again, if sound — would also suggest that chlorhexidine would have a similar nootropic effect if it could cross the blood-brain barrier.)
The whole molecule is the ligand: when you state you are "trying to distinguish which part of these molecules is the ligand," I again state that the whole thing is the ligand.
The parts that bind to moieties in the active site vs. the parts that might not do so directly are equally important. In your example with amphetamine, I can assure you that the electron-rich conjugated aromatic ring is very important, even if you don't see hydrogen bonding. Remember, we are talking about overall steric and electrostatics here.
If you want a bromide ion, just use a bromide salt: that directly gives you Br^{-1}. Swapping a single atom in a molecule can drastically change PK/PD properties, so caveat emptor.
As for chlorhexidine, it's an antibacterial on the upper limit of breaking at least one of Lipinski's RO5, although that's not a showstopper. There is no guarantee at all that it would behave like a similar compound.
I know drink a cup of coffee is probably not the answer a lot of the nootropic heads are looking for; but I don’t think there are any silver bullets here.
https://www.wikihow.com/Make-Vietnamese-Coffee
Oh, the usual coffee is "Cafe Du Monde" (in the orange can).
skin rash or hives, blisters or peeling, mouth sores, trouble breathing or swallowing, fever, swelling in your legs, dark urine, yellowing of your skin or eyes, or swelling in your face!? And there's more: https://www.drugs.com/provigil.html
Modafinil/provigil might be worse than crack!
i also love fresh lemongrass/ginger tea, makes me feel relaxed, sharp and alert
https://www.teafame.com/benefits-of-lemongrass-and-ginger-te...