Small molecule cognitive enhancer reverses age-related memory decline in mice
pubmed.ncbi.nlm.nih.gov
pubmed.ncbi.nlm.nih.gov
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).
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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...
Odds 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.