Mescaline/Escaline/Proscaline and friends; pro drugs?

[RobotRipping]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763256/

from the study above:

In vivo studies on the metabolism of mescaline have shown that a large part of the mescaline combines with liver protein....

Ratcliffe and SmithThe have found 3,4-dimethoxy-5-hydroxyphenyethylamine as a minor metabolite of mescaline in humans....

Data suggest that mescaline may be converted into some other substance which is directly responsible for the effects on the central nervous system

Brain imaging showed mescaline selectively increases neuronal activity, especially in the striatolimbic systems in the right hemisphere.

though that is a great study about mescaline, i can't find anything like that on escaline or proscaline.

i've determined through numerous trials that vaporizing, plugging (and another's report) of nasal use are ineffective with escaline/proscaline. It is likely these drugs are acting on the body in a similar way as to mescaline, as they are functional analogues, but what metabolites are responsible for their action?

Has anyone been able to use mescaline through any other ROA other than oral?

If this is so, then i wonder what escaline is being converted into and more so wonder how much better that compound would be if it were synthed, would it be more potent, less duration, less body load perhaps? maybe more psychedelic? are there several metabolites that work together?

anyone have any ideas on what may be happening in the body with the mescaline analogues? there's hardly any research on this so speculation is about as good as i can find. I'll try to find if Nichols had anything to say about escaline, the pihkal reports seem a bit off on it compared to my experiences. I find mescaline and these mescaline analogues to be so fucking strange in terms of onset, duration, peak, and in their effects.

any info would be appreciated just for the sake of knowledge or point me to some studies looking at some mescaline analogues in particular. I know escaline has had some research on it but nowhere near as much as mescaline.

 

[Morninggloryseed]

Coffee isn't in full force yet, so post will be short, but remember this from PIHKAL....it may fit into this..

Some years ago I performed a fascinating series of experiments with another isotopically labeled mescaline derivative. This was beta-14C labeled material, which I self-administered on three occasions, at three different levels. One dosage was with 350 milligrams, a second a few weeks later was with 4 milligrams, and a third was a few weeks later yet, with about 60 micrograms. In each case, exactly the same absolute quantity of radioactivity was administered, so the metabolic distribution was equally visible. Only the weight dosage was different. Urinary analysis was run for each experiment for the presence of unchanged mescaline, and for the primary metabolite, 3,4,5-trimethoxyphenylacetic acid. The smaller the dosage, the proportionately larger amount of mescaline was oxidized to the inactive acetic acid, and the smaller amount was excreted in an unchanged state. It seemed to me that there might be a finite capacity of the body to oxidatively deaminate mescaline, and at larger and larger dosages, this capacity became increasingly depleted. Perhaps this is why mescaline requires such a large dosage to be effective in man.

 

[Solipsis]

Haven't they done experiments collecting other types of bodily fluids like cerebrospinal fluid after radioactive labeled mescaline was administered to subjects? It could answer what metabolites are formed before further metabolism and excretion...

I'd say it is very likely that analogues like escaline, proscaline, allylescaline and methallylescaline show similar plasma protein binding effects (something probably not *that* unique, but it must happen to a significantly larger extent than other drugs / psychedelics), but another question is how quickly this changes as we go from mescaline to for example the TMA's, or 3C-X or 2C-X or DOX compounds. For example it is possible that this happens mostly with the 3,4,5-substituted phens which is possibly the reason why they have such low potency.

Well that, and probably MAO-B breakdown as well, which is probably why 3C-X compounds are more potent (they too have a 3,4,5-sub configuration, but the alpha-alkylation probably prevents breakdown so they can get to the brain even after protein binding).

 

[RobotRipping]

I don't have access to the Nichols articles from home unfortunately so my research isn't going to go far today but http://en.wikipedia.org/wiki/Jimscaline is interesting and in some way may help to explain the differences in PEA in regards to potency, duration and effects. As well http://en.wikipedia.org/wiki/TCB-2 is another interesting one that came out of all this research.

This discovery that the side chain of the phenethylamine hallucinogens could be constrained to give chiral ligands with increased activity then led to the later development of the super-potent benzocyclobutene derivative TCB-2.[

from the tcb-2 wiki

The related benzocyclobutene analogs of mescaline, Tomscaline and Bromotomscaline also exhibit significantly higher potency than their parent compound.

so i guess there's a pattern there

just from experience it does seem like something particular to the 3-4-5 sub PEAs but the DOx series also have similarities with regards to onset and duration at least but are extremely potent. At this point, the chemistry and pharmacology goes way over my head so what's the deal with http://en.wikipedia.org/wiki/2CB-Ind then?

i guess i got sidetracked there but it kind of goes back to this (though i'm not sure how it all relates) in the original study i posted:

The 2,3,4,5-tetramethoxy derivative is somewhat more active than mescaline. The pentamethoxy analog is the most active, indicating that sidechain cyclization to the indole derivative may not be important for mescaline.

I wish i could bring this altogether but it's just not my area of expertise.

 

[Solipsis]

It is interesting but not relevant I think. Constrained analogues like jimscaline or TCB-2 are potent for another reason: the extra ring forces the structure to be in a conformation with rather limited degrees of freedom of movement.

The same principle was applied to LSD: the diethyl amide part is like the head of a deer with antlers, that can flop around. However it can only fit well in the receptor if the antlers are pointing in a certain direction. If the antlers can flop around, you can imagine that when an LSD molecule heads into a 5-HT2A receptor there is a chance that at that moment the antlers are facing the right way and a chance that they are facing the wrong way.
The dimethylazetidide is an example of a constrained LSD analogue that cross-connects the antlers so that they are relatively stuck in a position. That can seriously increase the odds that the molecule docks into the receptor successfully - binding and activating it. There are a few different stereoisomers corresponding with a few possible positions. One of them fits more ideally in the receptor than LSD itself.

This should provide a possible answer why 2CB-Ind is not that potent: apparently the position the 5-ring forces the amine chain in is not favorable for receptor binding. Just like there are lysergic dimethylazetidides that are more or less stuck in a way that is wrong for a fit in the receptor... making the odds of binding succesfully quite low.

The same applies to optical isomers. In some cases such as with amphetamine or ketamine both isomers have action (although different ones), but in most cases one isomer works well and the other not so much. Isomers can be separated / isolated so that you only have the form that fits well.

I think that the reason adding extra methoxy's to mescaline makes it more active is something like the binding proteins being shaped in a way that best fits 3 adjacent methoxies, but more than 3 may match badly allowing more free mescaline to act. OR: it has something to do with the tetra analogue fitting better in the 5-HT2A receptor which makes a lot of sense since the 2,4,5 substution is contained in it, even if there is an extra one on the 3. Now that I think of it, that makes a lot more sense to me... but it is possible there is a tradeoff, and the potency is a result of what the molecule fits in well plus what it doesn't fit in so well.
How a compound fits in 5-HT2AR matters, how it fits into enzymes like CYP isoforms, how it fits into MAO, and now plasma protein is added to that list. There are probably more. All of them together determine among other things how high the bioavailability is (I think esp. protein binding is associated with BA), how high the affinity and efficacy for the target receptor is, lipophilicity can determine how fast a drug arrives in the brain which in turn *can* have an effect on tachyphylaxis (acute tolerance) and general kinetics. So there are a lot of factors to be considered.

 

[bloodshed344]

I think that the reason adding extra methoxy's to mescaline makes it more active is something like the binding proteins being shaped in a way that best fits 3 adjacent methoxies, but more than 3 may match badly allowing more free mescaline to act. OR: it has something to do with the tetra analogue fitting better in the 5-HT2A receptor which makes a lot of sense since the 2,4,5 substution is contained in it, even if there is an extra one on the 3. Now that I think of it, that makes a lot more sense to me... but it is possible there is a tradeoff, and the potency is a result of what the molecule fits in well plus what it doesn't fit in so well.

If that were true, that it's more potent because it contains the 2,4,5 substitution, wouldn't that mean that the 2,4,5-trimethoxy analog of mescaline would be active? As far as I know it's not. And wouldn't that also mean that you could have 2,3,5,6-tetramethoxy 4-substituted phenethylamines that are espcially potent? But as far as I know they're not active.

I bet it's your first idea: The extra methoxy rings make it harder to metabolize. I read someone say that mescaline, being a primary amine shouldn't even be active at all and should be metabolized very quickly, but for some reason it is not. It must be these methoxys, I wonder how 2,3,4,5,6-pentamethoxyphenethylamine is on the duration. That would tell us a little bit about all this. Also I'd love to try some, wonder how the ratio of psychedelic/body high is for this one.

 

[RobotRipping]

^
Smythies and co-workers
(Smythies et al. 1967) employing a modified Bovet-Gatti profile,
have found that 2, 3, 4, 5, 6-pentamethoxyphenethylamine (4 9)
possesses an approximate activity of eight mescaline units in animal models

source: http://archives.drugabuse.gov/pdf/monographs/22.pdf page 11

can't find any mention of duration in humans unfortunately but if anyone wants to test it on me i'll do it for a few grand

that article also mentions many interesting things about mescaline analogues starting on page 27 (Mescaline Analogs: Substitutions at the 4-Position ) that relate to the discussion here. Jesus Christ i didn't realize how technical this gets or that so much is already known about such things. Most of it goes way over my head, as my background isn't in chemistry or pharmacology. It must be great to be on the forefront of this kind of research, not to mention possibly testing the drugs on yourself like Shulgin has.

I wonder why more of these interesting drugs haven't hit the RC market yet.

@Solipsis: thanks for the explanation with the antlers lol i'm a very visual learner and that makes it easier for me to grasp what's going on.

 

[Solipsis]

2,4,5-Trimethoxyphenethylamine is 2C-O and no it is not active but apparently it can potentiate mescaline. Perhaps because it occupies plasma proteins allowing more mescaline to roam freely.

However the alpha methylated analog of 2C-O is TMA-2 which is I think generally considered the best of the TMA's and it is the most potent of TMA# 1, 2 and 6 which are the three most prevalent ones.
Doesn't this tell us that 2C-O is probably too much of a MAO substrate, but one that is metabolized relatively quickly while mescaline's binding to MAO is less reversible? Or does the alpha methyl group enhance binding?

 

[any major dude]

My impression was that mescaline's metabolic pathway had to become saturated before enough was in the bloodstream & thusly the brain, to have an effect. It stands to reason that similar things like 2c-O may occupy the same cyp's & mao subtype thereby letting the mecaline slide on by.

I don't see why this wouldn't also apply to other 3,4,5 subbed PEAs, but a lot of those mescaline analogs seem a little funky pharmacologicaly, so who knows. They may well have active metabolites, but I doubt they're proper pro drugs