Im interested what 6-trifluoro-aMT would feel like.
But let's first see reports of 5/6-fluoro-aMT. I wonder why it hasn't been synthesized on a large scale. I mean they are strong MAO-A inhibitors but I have seen more dangerous chemicals pop up so that shouldn't be a problem.
I guess 6-TFM-aMT might be interesting. I'm actually also very interested in 5- and 6-Fluoro-aMT. I've also wondered why they are so scarce, I wonder if it has anything to do with the bad reputation of 5-MeO-aMT. I've actually wondered what alpha-TFM-Tryptamine or 5-MeS-aMT would be like.
The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.
The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.
The LSD pharmacophore is... touchy. A slight modification to the ergoline core throws the binding profile totally out of whack, but LSD itself has really high affinity for five receptors and relatively high affinity for another six. Dihydro-LSD is about 25 times less potent.
Honestly, its really not at all surprising to me that 2-Br-LSD is inactive as a hallucinogen. From everything I've read, 2-substituted tryptamines lose all affinity for 5-HT2A and instead are moderately selective for 5-HT1B, 5-HT1D, and/or 5-HT6, as either an agonist or antagonist, depending on the 2- substituent[1][2][3]. If anything, the fact that 2-Br-LSD is an antagonist without 2A affinity seems to confirm that at least some tryptamine SAR carries over to the LSD pharmacophore. More than ever, I'm interested in seeing some of these explored.
Someone please humor me, all opinions welcome with reasoning given.
Let me just start off saying that I have no formal knowledge of chemistry, just stuff that I've researched on my own. I am genuinely interested in it, but I'm not sure if I'll ever really end up taking any serious classes on it. I do like messing around with things though, and I just spent a little time putting this together mostly because I'm bored and thought it would be fun.
As I'm sure is quite clear to anyone here, A is tryptamine and G is DMT. The rest of the changes I made here may or may not seem a little random, but I was following a set pattern for them.
M is of course a piperidine analogue of tryptamine, which I thought to add because of experiments on another forum I read where people were trying to alter the metabolism of tryptophan first to form DMT, and then on a separate experiment to form that piperidine analogue by inhibiting aldehyde dehydrogenase and having the resulting compound formed from tryptamine being metabolized by MAO mix with supplement-increased levels of dimethylamine or piperidine, respectively, in the body. Now, I have no real idea if what they were doing is correct or if it would work just how they wanted, but they definitely did report altered effects when they gave it a shot, so I figure something is going on at least. The reason I was most interested by this is because their results found that the effects lasted for much longer, and that was something they had expected from the start, citing PCP and its analogues as an example of how piperidines can take much longer to metabolize than their corresponding amines as a reason to predict increased half-lives. So that's the reason for that.
I decided next to think about other ways to keep a chemical around in your body for even longer. I thought that maybe a good example to follow in that regard would be starting at scopolamine (pic), which is really not all that different from phenethylamine and tryptamine in structure relatively speaking, and try to continue down the path they took in the Edgewood Aresenal experiments, given that one of the goals of that was to make longer-lasting compounds to be used as chemical warfare agents. That's where the beta-hydroxy came from in my picture. I realize that that's actually a shorter version than what's on scopolamine, but what I had in mind was the next step between that and QNB (pic), which as far as I could tell actually lasts even a little bit longer than scopolamine can, which is already pretty long. That's also where the beta-phenyl came from, and why some of them have both the hydroxy and phenyl there. I have to ask, knowing as little as I do, is that still valid here? (Like, can you have both there?) Either way, that's how I arrived at that point. Obviously, I also didn't change them to tropanes and just left either the amines or piperidine structures there, and instead of the main phenyl I kept it an indole. From there I took it a step further to EA-3167 (pic), the compound made with the longest duration of effect, reaching a ridiculous 120-240 hours in delirium from an injected dose. That's where that last change comes from... I know it shouldn't be called pyrrolidine without the nitrogen atom, but I don't know what exactly it would be called. Is that the "cyclopentyl" in EA-3167's full name? Please correct me if I'm wrong. Anyway, I thought that just based on this alone if anything was going to increase the half-life of these structures that could be it.
So really the first thing I'm interested in is all that: am I even close to being on the right track here in terms of things that would lengthen the lives of these chemicals in the body? I know that I'm going at this in a very basic way and it's not the best way to understand it, but this is generally how I tend to learn things... just trial and error with what seems right and then getting feedback on why it is or isn't correct... so I thought I'd take it here to ask. Whether I'm right or not, if you have something to say, please do explain!
The main other thing I was wondering is how anyone here thinks these changes to the original structures of tryptamine and DMT might effect their activity in the brain and body. All I really have to go on is how I can relate them to different chemicals I recognize. H feels somewhat reminiscent to an indole-y diphenhydramine (pic). P makes me think of synthetic cannabinoids like JWH-018 (pic) which doesn't exactly make me feel too confident about the duration, but it does make me wonder about its potential activity. I also can't help but think about compounds like desoxypipradrol (pic) when I look at N, which I'm interested in particularly because of the duration but also from the effects. Anyway, I think I've made my point here.
So the second thing I'm wondering is, am I way off base here too or am I on my way to understanding some things? Also, what do you guys think just from what you know about what any potential changes in activity these things would have? Do you see any resemblance between these and other significant molecules that I've missed that might give over clues to how they would behave? Again, if you have something to say, please give reasoning for it so I can learn from it!
This is obviously, like I said, a very basic way to look at this stuff and I know I probably seem like I know very little of what I'm talking about. But I really am just curious about this stuff and wondering if what I've picked up on from my casual research really means anything at all, and also just what anyone thinks about these. Whether you're think they're good, useless, toxic... like I said, any opinions are welcome. And if you actually do read all this and respond, I thank you in advance for taking the time!
You forgot to draw the double bond between the 2 and 3 positions on the indoles.
So really the first thing I'm interested in is all that: am I even close to being on the right track here in terms of things that would lengthen the lives of these chemicals in the body?
Strictly speaking, yes. Then more bulk a molecule has, the longer its half life. But not all of the compounds you drew will be active as psychedelics. The structure-activity relationships of scopolamine, atropine, BZ and the like is different from the tryptamine/phenethylamines. Atropine and BZ and friends exert activity by blocking muscarinic acetylcholine receptors, whereas DMT acts as a serotonin receptor agonist.
given that one of the goals of that was to make longer-lasting compounds to be used as chemical warfare agents. That's where the beta-hydroxy came from in my picture.
The general theme with making long-duration compounds is avoiding hydroxyls as much as you can. Any groups that can give a liver enzyme a metabolic 'handle', to oxidise or stick sugar molecules on, is going to reduce duration. Also, adding OH groups increases polarity by encouraging hydrogen bonding, making the compounds less fat-souble.
I have to ask, knowing as little as I do, is that still valid here? (Like, can you have both there?)
Yes, carbon is tetravalent. It can have up to 4 things bonded to it. (Although, having 4 different things connected to a carbon makes the molecule chiral - for every 'chiral center' there are two molecules, like a left and a right hand, that cannot be overlaid in space and are mirror images of each other).
but I don't know what exactly it would be called. Is that the "cyclopentyl" in EA-3167's full name? Please correct me if I'm wrong. Anyway, I thought that just based on this alone if anything was going to increase the half-life of these structures that could be it.
Yes, a 5-membered cyclic carbon ring is a cyclopentane, or cyclopentyl group. Typically, because alkanes and cycloalkanes are nonpolar and not very reactive, they can be 'glued on' to increase duration. The caveat, of course, is that too much blk might stop the compound from binding properly.
Shuklgin talks a bit about this in PiHKAL.
AEM said:
The extension of the two-carbon chain of mescaline by alpha-methylation to the three carbon chain of TMA approximately doubled the potency of the compound. And it was felt to be a completely logical possibility that, by extending it one more carbon atom, to the four carbon chain of α-ethylmescaline, it might double again. And following that logical progression, the doubling of potency with each additional carbon atom, the factor would be 2 to the 7th power by the alpha-octyl (or 256× that of mescaline, or a milligram as active dose) and with a side chain of a 70-carbon alkyl group (α-heptacontylmescaline) it would take just a single molecule to be intoxicating. This was rich fantasy stuff. As an active compound, just where would it go in the brain? With an 80-carbon side-chain, would one-thousandth of a single molecule be enough for a person? Or might a single molecule intoxicate a thousand people? And how long a chain on the alpha-position might be sufficient that, by merely writing down the structure on a piece of paper, you would get high? Maybe just conceiving the structure in your mind would do it. That is, after all, the way of homeopathy.
Maybe it was just as well that this added two-carbon side-chain with lowered activity was already enough to disprove the doubling pattern. But by the time this non-activity had been learned, the alpha series had already been pushed out quite aways. [...] But since the first of these, AEM, was not active, there was no enthusiasm for tasting anything higher. This family was never published; why publish presumably inactive and thus uninteresting material?
Compound M has been made, it is known as pip-T. The one with a 5-membered ring, pyr-t, is known and not particularly promising at all. 5-MeO-pyr-T caused some wierd fugue/blackout states.
TiHKAL said:
The piperidine material, pip-T, is made via the glyoxylamide (mp 182-183 °C) which is reduced with LAH to the target amine (mp 149-150 °C, HCl salt 220-221 °C). The morpholine analogue also came to be via the glyoxylamide (mp 187-188 °C) and the reduction to the amine which can be an oil, but which has been reported to have a mp 145-147 °C. The only trials I know of with either of these is with mor-T which, as the fumarate salt, had no effects at all upon the i.m. injection of a 30 milligram bolus.
So the second thing I'm wondering is, am I way off base here too or am I on my way to understanding some things? Also, what do you guys think just from what you know about what any potential changes in activity these things would have? Do you see any resemblance between these and other significant molecules that I've missed that might give over clues to how they would behave? Again, if you have something to say, please give reasoning for it so I can learn from it!
i always wondered about this one. seems so obvious.... the amphetamine version of mephedrone. i assume there must be a good reason that its not around, but i do not know what that reason might be.
Strictly speaking, yes. Then more bulk a molecule has, the longer its half life. But not all of the compounds you drew will be active as psychedelics. The structure-activity relationships of scopolamine, atropine, BZ and the like is different from the tryptamine/phenethylamines. Atropine and BZ and friends exert activity by blocking muscarinic acetylcholine receptors, whereas DMT acts as a serotonin receptor agonist.
Yeah, I figured most of them wouldn't be active as psychedelics, or at least would have a considerably lessened chance to as it went on.... I was really more concerned about the duration anyway so that's okay with me, I just thought it would be cool to draw them with the indole group instead of the phenyl like those anticholinergics have. I figured it couldn't hurt.
I actually keep coming across this frustratingly obscure reference that hyoscyamine is a serotonin antagonist too, which does make me wonder if a change like that would possibly still keep some serotonin receptor affinity (good or bad), but I really can't find any actual source of that information, just mentions.... Any idea about that?
The general theme with making long-duration compounds is avoiding hydroxyls as much as you can. Any groups that can give a liver enzyme a metabolic 'handle', to oxidise or stick sugar molecules on, is going to reduce duration. Also, adding OH groups increases polarity by encouraging hydrogen bonding, making the compounds less fat-souble.
Yes, carbon is tetravalent. It can have up to 4 things bonded to it. (Although, having 4 different things connected to a carbon makes the molecule chiral - for every 'chiral center' there are two molecules, like a left and a right hand, that cannot be overlaid in space and are mirror images of each other).
Yes, a 5-membered cyclic carbon ring is a cyclopentane, or cyclopentyl group. Typically, because alkanes and cycloalkanes are nonpolar and not very reactive, they can be 'glued on' to increase duration. The caveat, of course, is that too much blk might stop the compound from binding properly.
Shuklgin talks a bit about this in PiHKAL.
Compound M has been made, it is known as pip-T. The one with a 5-membered ring, pyr-t, is known and not particularly promising at all. 5-MeO-pyr-T caused some wierd fugue/blackout states.
Ah, that indeed doesn't sound very promising.... Still pretty neat to think about though. I wonder what activity caused such the drastically different effects compared to related compounds? It definitely doesn't sound like the best path to take though. But thanks again!
Woah, that's a neat one... and pretty interesting that it's a stimulant. I can definitely see the similarities, and I would compare it to desoxypipradrol too just like I did with some of the ones I drew. That certainly gives me something more to think about, thanks for that!
And thanks one last time for a very helpful and informative response!
Psilocin is already substituted at the 4 position with a hydroxyl group. 3-methylmethamphetamine isn't the reduced form of mephedrone, 4-methylmethamphetamine is, and probably has neurotoxic and monoamine oxidase inhibiting and generally not very good effects.
One could hope it safer than the 4-methylated homologue. . . might actually fell pretty nice, but it's up in the air whether it'll be entactogenic at all.
Not that I claim to understand the subtleties of MAO-A or anything, but if metabolism to an MPP+-like compound were indeed a danger, wouldn't that happen already with naratriptan? According to a paper on triptans and their metabolism and possible interactions[1], naratriptan undergoes metabolism by MAO-A, P450 (which specific P450 has not been elucidated), as well as renal metabolism. The creation of MPP+ from MPTP on the other hand, is via MAO-B[2]. Perhaps the creation of MPP+-esque compounds from MPTP analogues requires some specific mechanism of MAO-B. Either way, I've not heard of naratriptan being a serotonergic neurotoxin, so I'm guessing it probably wouldn't happen with buildersoftime's compound either, unless I'm missing something here. The only mechanism I could think of that would make naratriptan safe and the compound under discussion not safe would be that naratriptan has no SERT affinity while buildersoftime's compound does, since the DAT is also required for MPTP-induced neurotoxicity[2]. Of course, I could be missing a million other things here, if I am, please let me know!
Not that I claim to understand the subtleties of MAO-A or anything, but if metabolism to an MPP+-like compound were indeed a danger, wouldn't that happen already with naratriptan? According to a paper on triptans and their metabolism and possible interactions[1], naratriptan undergoes metabolism by MAO-A, P450 (which specific P450 has not been elucidated), as well as renal metabolism. The creation of MPP+ from MPTP on the other hand, is via MAO-B[2]. Perhaps the creation of MPP+-esque compounds from MPTP analogues requires some specific mechanism of MAO-B. Either way, I've not heard of naratriptan being a serotonergic neurotoxin, so I'm guessing it probably wouldn't happen with buildersoftime's compound either, unless I'm missing something here. The only mechanism I could think of that would make naratriptan safe and the compound under discussion not safe would be that naratriptan has no SERT affinity while buildersoftime's compound does, since the DAT is also required for MPTP-induced neurotoxicity[2]. Of course, I could be missing a million other things here, if I am, please let me know!
