• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio | someguyontheinternet

The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

Status
Not open for further replies.
Does anyone know how exactly Gramine mediates its toxicity ? Wikipedia says : "Gramine is a norepinephrine reuptake inhibitor in synaptic vesicles.[citation needed] Resulting effects of extra norepinephrine raise blood pressure and heart rate."

What i dont get is why the inhibition of norepinephrine reuptake is considered toxic in this case but not when its stuff like methylphenidate that inhibits the reuptake.
 
Without reading much about gramine, I think this is a case of "the difference between medicine and poison is in concentration" so to speak. Stimulants of all kinds could be considered toxic because an overdose can lead to death. In this case though it's not considered a medicine, only a toxin, hence the wording "mechanism of toxicity" rather than "mechanism of action".
 
Hmmm if it's not sometime specific to this chemical Gramine (a toxic metabolite for example) the mechanism of toxicity could be excitotoxicity from increased adrenaline transmission at a high dose? This should be possible with methylphenidate if the dose is high enough?

Excitotoxicity is typically dose dependent (you won't get enough excitability at a low dose to cause damage) where as other kinds of metabolism toxicity could be possible at any dosage but the extent of the toxicity correlates with the dosage.
 
I guess i just have to try it myself. Just gotta start very low and work my way up. I dont think its that toxic because if you compare the molecules its almost identical to dmt just with a shorter sidechain.

Fortunately i already have experience with noradrenalin overloads and know what it feels like.

This just pisses me off because in literature the pharmacology seems to be well known but you cant find anything about it on the internet.
 
It's actually closer to phenethylamines if you look at it - a 2 carbon spacer between the tertiary nitrogen and "benzene ring" if you ignore the fact that it's an indole derivative, which also explains why it has NE reuptake inhibiting properties.

I'd be cautious if I were you though. Just because there's little information on the possible toxicity outside of NERI doesn't mean it isn't dangerous/harmful. Maybe someone with more knowledge about gramine could chime in as I'm only speculating. But yes, start very low.
 
A few questions about Shulgin.

1. How did he know the compounds he made were actually the compounds he made. I guess he had an NMR machine but I can't see anywhere in pictures of his lab.
2. Speculations on his dosing method/schedule to trial out a completely novel compound which could be active at 10 micrograms or 10 grams.
3. How did he tackle purification of compounds which might have a few impurities in them e.g overbromination of 2-CB?
 
NMR machine is not really something you keep in your lab. It's usually in a separate room if your institution has one. Anyway, there are many ways to identify a compound's structure, I'm sure he had that under control.

Not many substances are active in the nanogram range so I guess one could start from the low end of micrograms and (on separate occasions) move up from there increasing the dosage slowly. This is what I would have done if I had no idea how active the compound is. Usually the active dosage is at least somewhat similar to the compounds close relatives, so you can predict whether it'll be more of a microgram or milligram range. I don't know what he actually did though, but I do believe he didn't just blindly eat grams of new product.
 
belligerent drunk said:
NMR machine is not really something you keep in your lab. It's usually in a separate room if your institution has one. Anyway, there are many ways to identify a compound's structure, I'm sure he had that under control.

Not many substances are active in the nanogram range so I guess one could start from the low end of micrograms and (on separate occasions) move up from there increasing the dosage slowly. This is what I would have done if I had no idea how active the compound is. Usually the active dosage is at least somewhat similar to the compounds close relatives, so you can predict whether it'll be more of a microgram or milligram range. I don't know what he actually did though, but I do believe he didn't just blindly eat grams of new product.
Click to expand...

I said micrograms lol, anyway though I don't think predicting from similar compounds a dosage range is completely safe either as there are many examples to prove this. For example, alpha methylation substitution increases potency of some compounds by an order of magnitude, like the DOX series, likely because of much increased resistance to enzymatic oxidation. If one had assumed just a slight increase in potency from this substitution and took a slightly smaller dose of the methylated version than usual, that person would be in for a long ride.
 
I was just saying that starting from the nanogram range would be redundant in my opinion, didn't mean that you suggested it. Anyway, you're right. Just assuming the potency of a compound could prove to be dangerous especially in substances that can be lethal in OD. My point was that if you account for the known changes (like the example you gave, methylation) and the active dosage of a related compound, you can get an estimate. If a very similar compound is active at 500 mg, there's a very big chance that your new compound won't be active at 5 µg. What I had in mind was more like starting from 2 orders of magnitude lower than the "possible estimated" active range.

What would you do?

EDIT: a good example to counter my argument is phenibut and baclofen. A para-chloro addition shifts the active dosage 2 orders of magnitude lower. Still though, baclofen is active in the milligram range so start from micrograms would not be problematic.
 
If it's a completely novel compound which no one has ever ingested before, I'd probably first examine it to see the potential causes of toxicity, then go 3 orders of magnitude lower than the expected range and then double the dosage every say 24 hours assuming the molecule has reasonably metabolically labile to have a half life way shorter than 24 hours. I think there are only very few drugs which are inactive at one dose and then toxic or lethal at double the inactive dose. Any thoughts on the purification question?
 
How would you examine the potential toxicity? I'm not a pharmacology expert, but I think there are (even recent) examples of compounds with unexpected toxicity which went by unnoticed until some people messed up their body/receptors. Unless you have rodents or primates to torture, I think just looking at the structure will give you less information about its possible human toxicity. Correct me if I'm mistaken.

Regarding purification, there are many ways to separate compounds. Column chromatography? I personally haven't worked with compounds of different degree of halogenation on an aromatic ring, but I guess you could separate them chromatographically as that's a pretty convenient way of purifying synthesis products. Cheap and fairly easy too.
 
Last edited:
I was actually thinking rodents would be a good indicator of at least acute fatal toxicity, although some people will definitely object to this morally. If a rodent can survive x amount of compound then a human is very likely to survive that (or even 10 times that amount) for the most part. By examining potential toxicity I meant doing nothing too in-depth as with these novel compounds they are totally unpredictable, but for example if it has a phenethylamine skeleton in it, you could predict that it'll have vasoconstrictive properties at extremities, pulmonary hypertension etc. So you could obtain a rough indication of what risks definitely exist. That is not to say there are unpredictable risks.
 
essentially the way described above... started out at microgram doses and doubled every day or three until he reached the active dosage. then once he found the active dosage, he would share the chemical with his "research team" (not all of the qualitative comments in PiHKAL are written by ann and sasha). the research team wouldn't titrate up in the same way. which led to problems a time or two... (check the qualitative comments under... i forget if its one of the TOMs or one of the TOETs but its one of 'em. one of the research crew ended up being unusually sensitive to one of those chemicals).

his goal was to create more potent drugs, the mindset being that the physical sideeffects aren't necessarily caused by the 5HT2A activation. so in theory drugs that are psychedelic at lower doses would be less likely to have peripheral action. he admitted that this is not a foolproof theory, but in the absence of anything else to go on it seemed to him to be the most sensible way to proceed. so, many of the drugs in PiHKAL and TiHKAL that don't have active dosages listed may actually be active at higher doses -- shulgin just never hit the active dosages in his titration procedure and gave up once he realized that they were going to be less potent than the parent compounds.

particularly a lot of the MDxx analogues in PiHKAL are probably active at the sub-1gram range, but since they were so much less active than MDMA/MDA and their cousins that he never bothered reaching the active dosage.

and probably a lot of the mescaline analogues are active but at rather large dosages.
 
He had an NMR machine. He often used re-crystallization as a means of purifying both intermediates and finished products.
 
A calculator estimates trigonometric functions by using many terms in the Taylor series for the respective function.

Similarly, how does a computer energy minisiming a structure? How do you even calculate the potential energy for a structure?
 
Why is it that if a molecule is taken up by SERT, there is a good chance it'll be taken up by DAT. In other words, lots of substituted phenethylamines are taken up by both. So surely we would expect BOTH the endogenous ligands to be similar in structure to phenethylamines. Dopamine is similar, but 5HT seems way different with an indole ring instead.
 
aced126 said:
Why is it that if a molecule is taken up by SERT, there is a good chance it'll be taken up by DAT. In other words, lots of substituted phenethylamines are taken up by both. So surely we would expect BOTH the endogenous ligands to be similar in structure to phenethylamines. Dopamine is similar, but 5HT seems way different with an indole ring instead.
Click to expand...

Well serotonin isn't THAT different. There's basically one extra methylene group between the basic nitrogen and the benzene ring, the other ring with the aromatic nitrogen could be viewed as a ring and aliphatic chain substitution, which is often done on phenethylamines. Of course, indole is quite different from benzene, but structurally tryptamines look quite similar to phenethylamines. Gramine is a good example, imo, because it lacks the extra methylene group and seems to behave like a phenethylamine despite looking closer to tryptamines at first glance.
 
Status
Not open for further replies.
Top