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2CLisaB?

Seems like an unnecessarily complex way to cyclically substitute and shield the amine (from metabolism etc), I don't see why you couldn't achieve the same with a pyrrolidine a la pyr-tryptamine:
https://en.wikipedia.org/wiki/Pyr-T

Although, pyr-T appears to be remarkably unpleasant but I recently thought of an explanation, I think it has to do with the metabolism..

Substituting the amine on a psychoactive PEA seems to really detract from potency, so I don't think I would be that hopeful about pyr-2C-B or 2CLisaB. Definitely not one i would custom synth. Then again, the phenmetrazine analogue or related of 2C-B has been made and IIRC found to be incredibly potent... but that's a little different I'd say.

Some THIQs are psychoactive like a number of pharmaceuticals and alkaloids found in peyote etc, but they are not so simple as the one in this molecule..
 
What is there to speculate? As a chemist I can draw you hundreds of such chemicals in an hour but you will learn nothing by looking at them. We do not even know how the active species look like that interacts in the brain. You might want to have a look at the talk from Jesper Kristensen from Copenhagen University who gave a very impressive talk about what we do and what we don't know: https://www.youtube.com/watch?v=AmuuS4gxOVc
 
There can be value in speculation, just don't take it as fact. It can help narrowing down which hypothetical compounds may be more interesting than others. You use SAR based on known substitutions, for example most N-substituted PEA psychedelics other than PEA empathogens which follow different SAR, do not appear to be that interesting if you read PiHKAL.

So, it's still worth noting that putting even one methyl on the amine lowers the potency of a PEA about ten-fold... what makes up for that is if you substitute not a methyl but something like certain kinds of N-benzyl or NDEPA which overlay with a pharmacophore that extends beyond tryptamines and phenethylamines that some lysergamides like LSD also relate to.

Nobody asked about a certain calculation of the effects, but you can still try to extrapolate what is known. Pioneering is a combination of on the one hand trying variations that may not quite follow all SAR predictions because as you say: we don't really know and you might find novel compounds that way... but on the other hand, it's reasonable to speculate in order to filter a little bit in what is expected to fit in current models at least somewhat... because you can't randomly try everything, it's costly so ridiculous. Also speculation helps with motivating and dreaming about what has not yet been done.

So not saying this couldn't possibly have action, it very well could...

If THIQs like that are active by virtue of that particular moiety, it's very curious that it is hanging off a 2C-B structure which is not likely to have much to do with it and may very well be posing limitations on the actual THIQ compounds. It would sort of be a hybrid of drugs which is generally not a good idea, certainly not to start discoveries with. If that is not the case and it is actually the complete molecule that is active as a psychedelic you would expect it to follow some of the rules you also see the N-benzyl and NDEPAs and lysergamides following because those demonstrate at which positions certain groups are tolerated, not tolerated or actually critical to the activity.

In this case it actually looks alright because it is basically a cyclized and constrained N-benzyl group so it could be NBOMe-like. Guess I hadn't really thought about it like that. It would probably be improved by a methoxy or fluoro on the THIQ aromatic ring just like NBOMe's > basic N-benzyls like N-benzyl-2C-B which has been tested.

It's really extreme to suggest that SAR speculations are completely pointless in any stage. I must admit that it would be quite interesting to see whether the NBOMe likeness is good enough for it to be quite active or if the tertiary amine just isn't tolerated whatsoever.

I just think that the latter is the case because of Shulgin writing things like this:

N,N-Dimethylmescaline has been given the trivial name of Trichocerine as it has been found as a natural product in several cacti of the Trichocereus Genus but, interestingly, never in any Peyote variant. It also has proven inactive in man in dosages in excess of 500 milligrams, administered parenterally. This observation, the absence of activity of a simple tertiary amine, has been exploited in the development of several iodinated radiopharmaceuticals that are mentioned elsewhere in this book.
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Tried checking the Shulgin Index but I'm not really seeing interesting entries for tertiary amines at a quick glance.

If you're not presumptious about what we don't know, I'm not presumptious about what we do know - deal? :)
 
I know this thread isn't about the video that drseltsam posted, but I'm wondering from their findings on NBOMe metabolism of the 5-methoxy, if restraining that methoxy into a ring (hemifly style) wouldn't theoretically hinder that metabolism and cause it to be orally active?

I guess that's what one of the audience is asking about in the end. Going by that lecture, 25CN-5-hemifly-NBOH sounds like something that would be interesting to explore.
 
I don't see why the 5-methoxy would suddenly be such a target for metabolism that it renders the compound orally inactive while non-N-substituted PEAs like all 2C-X don't have that problem. The N benzyl function has nothing to do with the 5-methoxy and it is N-benzyl cleavage through first pass metabolism from oral administration that is considered to be the reason for them being mostly orally inactive. :) That metabolism yields the parent PEA (usually the 2C-X of course, they are NBXed mostly) which is much less active and therefore goes unnoticed.

Your proposed compound would not be named that way since the 25 stands for 2,5-dimethoxy and you have replaced your methoxy on the 5.. It would be more like 2CN-5-hemifly-NBOH or to avoid confusion perhaps 2C-CN-5-hemifly-NBOH. ;)
 
Solipsis said:
I don't see why the 5-methoxy would suddenly be such a target for metabolism that it renders the compound orally inactive while non-N-substituted PEAs like all 2C-X don't have that problem. The N benzyl function has nothing to do with the 5-methoxy and it is N-benzyl cleavage through first pass metabolism from oral administration that is considered to be the reason for them being mostly orally inactive. :) That metabolism yields the parent PEA (usually the 2C-X of course, they are NBXed mostly) which is much less active and therefore goes unnoticed.
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I get what you mean, and that's what I always heard too. But did you see the lecture by that cimbi guy in the youtube video drseltsam posted? They seem to have found out that the methoxy at the 5 position on NBOMe's/NBOH's are glucuronidated extremely quickly by first pass metabolism, and that's what makes them orally inactive, not N-benzyl cleavage.


Solipsis said:
Your proposed compound would not be named that way since the 25 stands for 2,5-dimethoxy and you have replaced your methoxy on the 5.. It would be more like 2CN-5-hemifly-NBOH or to avoid confusion perhaps 2C-CN-5-hemifly-NBOH. ;)
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Ah, yeah, makes sense :)
 
Oh apologies I missed that - will check, it's very curious that a substitution on one end of the molecule causes it to be metabolically targeted on the other end... I wonder if the glucuronidation is limited, and 2C-X doses can afford losses from glucuronidation at that position while the NBOMe's at their doses cannot.

I assume these guys know what they're doing, but are they sure it's not happening on the benzylic methoxy which makes more sense since that one is absent in 2C-X? If that was a mass spectrum you wouldn't see a difference, only if you study the mass of the fragments..
I guess they checked that the radioactive methoxy was not cleaved, but it is unclear in the presentation - never mind it was tested... I'd like to contact the guy about it and ask if he has an explanation for the apparent increase in affinity for those enzymes if that is the explanation left for his conclusion - oh ok its much more lipophilic, interesting.

So what causes NBOMe's to be orally active in some people may be the key to try to also achieve it in everyone else - enzyme inhibition?

Cool I was at OPEN foundation psychedelics convention but not the more recent one..

And yes! I'm not sure which compounds they actually tested but hemifly would be my bet as well.. :) But possibly if you make a hemifly the liver enzymes still have such high affinity and will just start chomping on the second best metabolic site only a little more slowly, ad infinitum.

He says 25CN-NBOH is considerably more metabolically stable though - and to be fair it is indeed probably less lipophilic than 25B-NBOMe. And also apparently it is doubtful that the compound is psychedelic..

But please! I really don't want this kind of compound surfacing in the wild... :(
 
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Yes, it's really wierd about that metabolism thing, I was quite surprised too :)

Maybe you are right and stuff like that is too dangerous on the RC scene (25I and 25B already is imo) But if NBOMe's were orally active I think they might actually be safer, because you wouldn't have those uncertainties about dosing, as in: not knowing how much was actually absorbed in the mouth or nose. Then again, it seems to be the super high affinity to HT2a that also causes such high degrees of tolerance, which imo is also one of the dangerous parts of NBOMe and the like, so oral activity of cause wouldn't make them completely safe - at least not for binging.

Something like 2C-CN always intrigued me, it's said to also have a really high affinity for HT2a compared to other 2C's - but then again, high affinity doesn't neccesarily a good psychedelic make, qualitatively.

Some kind of enzyme inhibitor might work if what they found out is true, but it sounds extremely dangerous to me :)
 
Incunabula said:
Some kind of enzyme inhibitor might work if what they found out is true, but it sounds extremely dangerous to me :)
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lol you're probably right, if this https://en.wikipedia.org/wiki/Crigler–Najjar_syndrome is a good demonstration of what happens when you don't have working UDP glucuronosyltransferase, it's not pretty...

Do people really get that unpredictable trip intensities from buccal/sublingual administration of blotter?

Another problem is that making them orally active takes away the possibility to take a blotter orally to avoid potent NBOMe effect if you expect to have LSD blotter. Then again ideally people would reagent test, but the reality is that people are going to take blotter without having that available..

And apparently making the compound more hydrophilic helps a whole lot, so I guess if you calculate the log P of known active types of these compounds and perhaps modify them a little to make the lowest log P compound, and even if it is a bit less active at least it might have a shot at oral activity, because of lower affinity for liver enzymes..
At least that is what I take away from that talk which suggests that oral activity for most of those compounds is hopeless because liver enzymes just like them so much, and protecting a group does not really change that but changing the log P should.
 
Solipsis said:
Do people really get that unpredictable trip intensities from buccal/sublingual administration of blotter?

Another problem is that making them orally active takes away the possibility to take a blotter orally to avoid potent NBOMe effect if you expect to have LSD blotter. Then again ideally people would reagent test, but the reality is that people are going to take blotter without having that available..
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Thinking about it, it was just an assumption I made. People do seem to have pretty consistent trips from buccal/sublingual, so yeah, tweaking the NBOMe/NBOH's structure to be orally available, is probably a really bad idea, unless the safety profile is somehow changed at the same time to match that of the lysergamides, like a better dose/response curve etc.
 
Interesting thoughts :) I still would hold that speculation is not worth a lot. I guess the only way of knowing something is by testing it ( thank you captain obvious!)

I worked in the field of molecular calculations for several years and if I were to do research there I would do it something like this:

Define a goal what you want to get from your compound. E. g. If you read the thesis where the NBOMes where introduced it is clear the the only aim was to produce a specific ligand for the HT2C receptor. This has a high scientific value but makes it evident why they suck as drugs.
If you figured out what you want to get I would propose to train a neutral network to come up with suggestions. Human intuition is fun but I for these problems computers are superior.

These suggestions are simulated against the known livers enzymes to get an idea how they are processed and what candidates you run against the receptors.

The outcome of this is probably not reliable as the models are not sufficient or you do not have the compute power to solve them and you end up testing like Shulgin did it ;)
 
Whether it is more helpful or harmful to speculate also depends on what is intended... in the case of a wildly novel substitution it's all you have anyway, apart from using software to calculate comparisons with known structures or using receptor models. I think it's safe to say that nobody is seriously expected to custom synth this compound any time soon from the tone of the OP and the sheer amount of intellectual masturbation compared to actual development, but even if it hypothetically would be on the table, as mentioned before speculating is what drives a rationale to choose investigation of one compound over another. And it was a request to speculate... no it is not really reliable, there are a lot of limitations and SAR is notoriously fickle and erratic, but to leave it at that is very much a non-answer.
 
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