I Like to Draw Pictures of Random Molecules

[aced126]

I know: I said apparently on tryptamines much more freedom is allowed than on lysergamides.

Maybe with 2,4-dimethylazetidine you won't see huge differences between isomers but I bet that at some point if the alkyl chains get longer the conformation becomes a problem and there would be countless ways to constrain the antlers together using bridges / rings which would still tell us something about whether DPT analogues work better when the antlers are tied together or spread apart, or bent. So comparing spatial conformations would still be interesting a la LSZ even if there is much less of a small particularly shaped pocket?

Again: the metabolism might be a concern, or another reason why Pyr-T was so bad...

Oh yes, I see what you mean. I just thought you might be confusing the amidergic nitrogen with the aliphatic nitrogen of LSD...never mind.

 

[Solipsis]

@ anticholinergics... actually I thought the mention of DiPT having effects on hearing but also suggested on the vestibular organ quite interesting and this might cause certain similar ones and perhaps Pyr-T to be dizzying and icky. But Pip-T isn't even active and I don't really understand the reasoning behind comparison with tolterodine which has diisopropyl already. Yet even if DiPT can make some people wobbly I gotta say I found it rather pleasant on the body, however I didn't take my dosages very high.

The Pyr-T concerns are to be taken seriously I'd say, but at the same time I got this feeling that dimethylazetidine isn't actually that similar to pyrrolidine. Compared to LSD, LSZ appears to behave rather similarly and not like say LSM. For something that should look a bit like DET, it seems to me that Pyr-T and dimethylazetidine-T are rather opposite conformations.
For me dimethylpyrrolidine is like a much bigger question mark but I'm on the pessimistic side with that one. So better aziridine then or dimethylaziridine? D: with the amide in lysergamides apparently aziridines are quite unstable but afaik it matters a whole lot that it is not a type of amide in the tryptamine version and could be stable. *Perhaps* it's better though if the 4-HO version isn't made to absolutely minimize it reacting with itself but I can't really prove it.



The previously suggested azetidine by Jonneh is clever, especially the idea to try and avoid Pyr-T similarity... but I fear that it's a problem that it constrains the amine function to be straight from the indole with hardly any flexibility...
Fortunately it seems looking at LSD that it might actually be optimal? Maybe the distance isn't though, or maybe it is - even better than LSD in that regard.. :D

 

[Jonneh]

I had a look at a couple of binding models for LSD and a tryptamine to the 5-HT2a receptor. Who knows what receptor might be mediating the nasty, weird or interesting effects we're discussing, but it's a start.

LSD ................................................................................ a tryptamine ................................................................

It's clear from the model that what one might expect to be analagous positions (the 6-position nitrogen in LSD and the amine nitrogen in tryptamines, for example) are actually not. The whole indole has flipped, for starters.

Anyway, Pyr-T might not be psychedelic because the fat ring doesn't fit inside the space defined by the Asn343 residue, a least not in a way that also allows parts of it to hydrogen bond to the Asp155, and nestle in with Phe340 and Ile152. The diethyl of LSD is off to the side, not doing much, so I'm not sure the azetidine in LSZ is analagous to things hanging of the amine group in tryptamines.

Curiously, the tryptamine ligand they use (for its rigidity and therefore reduced uncertainty), 3-(N-methylpyrrolidin-2-ylmethyl)-5-methoxyindole, has a five-membered (pyrrolidine) ring at the amine, although positioned in such a way that the whole chain is shorter than in the case of Pyr-T.

I think your azetidine analogue should fit, although one of the methyls is probably redundant. It doesn't look like the amine nitrogen in tryptamines is doing much functional legwork as far as binding is concerned, so as long as something is hanging off it in the vicinity of that aspartate residue, small variations in distance from the indole should be tolerated.

It's only one receptor, but it's a test they really ought to pass.

 

[aced126]

Where did you obtain those models from?

 

[Solipsis]

That tryptamine looks off... speaking for the more typical ones like DMT, it seems unlikely that the molecule is flipped compared to LSD (just look at the indole nucleus) - and this one was previously posted on BL showing 5-MeO-DMT to bind relatively similar to how you have LSD modelled there, and has the same pi-stacking and the 5-MeO interacts with SER239 making it not flipped but basically oriented the same way:

 

[Jonneh]

Where did you obtain those models from?

They're from a Nichols paper from 2002.

That tryptamine looks off... speaking for the more typical ones like DMT, it seems unlikely that the molecule is flipped compared to LSD (just look at the indole nucleus) - and this one was previously posted on BL showing 5-MeO-DMT to bind relatively similar to how you have LSD modelled there, and has the same pi-stacking and the 5-MeO interacts with SER239 making it not flipped but basically oriented the same way

That's funny, because the binding of serotonin modelled in a separate study pretty much agreed with the Nichols model above, and the Nichols group only used an exotic tryptamine because of its rigidity - as far as I can see they expected it to reflect the binding of other tryptamines. Well, it's perfectly possible that different tryptamines could bind in different ways, although I would expect 5-MeOs to form their own cluster of higher inter-relatedness in terms of biding conformation. Perhaps they don't always, and that explains why some 5-MeOs don't show the 'typical' 5-MeO dodginess (5-MeO-DALT/MiPT vs 5-MeO-DMT/AMT, for example).

In the case that our new tryptamines bind like 5-MeO-DMT, the azetidine would be the congener of something hanging off the 6-position nitrogen in LSD (cf. MALT and AL-LAD). The azetidine in LSZ is still very much its own thing, I think (and perhaps resistant to change by dint of its interactions with other receptors, or perhaps it is interacting with Gln216 and/or Val235).

Well, back to old-fashioned Linnaean heuristics then. Fine by me!

 

[Solipsis]

I guess the other model was quite amateuristic, this:
http://scholarsresearchlibrary.com/JCMMD-vol5-iss1/JCMMD-2015-5-1-45-57.pdf
(page 55)

is consistent with Nichols, showing DMT so it wasn't a fluke..

You think something like Pyr-T obscures the amine from critical interaction with the asparagine residue? Because that may mean none of these constrained bridges are a good idea and that the tryptamine substitutions would need to 'spread their legs' for the money shot to put it bluntly? Might also explain why dipropargyls which mingle and stick to each other are no good?

Very confusing though, I already thought that tryptamines, lysergides, 2C's, mesc, NBOMe's at least were a bit skooched up compared to each other making SAR different but that it would be as bad as major flips and jumps really fucks with understanding of SAR! Trying to hybridize SAR relations would be all the more problematic.

 

[Jonneh]

You think something like Pyr-T obscures the amine from critical interaction with the asparagine residue? Because that may mean none of these constrained bridges are a good idea and that the tryptamine substitutions would need to 'spread their legs' for the money shot to put it bluntly? Might also explain why dipropargyls which mingle and stick to each other are no good?

That would be one possibility, and another would be that (even in the absence of direct interaction) the asparginine defines a space which the pyrroline is too big for (given its inflexibility), thereby preventing whatever is hanging off the amine from interacting with other residues, like Asp155. Both guesses are weighted heavily by our lack of active examples - a strong prior indeed. There might still be room for an aziridine or even azetidine - even though they might need to bend over to be with the Asp, to continue your lolworthy analogy. I think the leg-spreadability matters more than bottom-heaviness (cf. 4-HO-DSBT, which is pretty potent for all its bulk).

Very confusing though, I already thought that tryptamines, lysergides, 2C's, mesc, NBOMe's at least were a bit skooched up compared to each other making SAR different but that it would be as bad as major flips and jumps really fucks with understanding of SAR! Trying to hybridize SAR relations would be all the more problematic.

Looking at those Chilean models for the binding of DMT, I notice they get wildly different results when assuming rigid versus flexible residues. The flexible assumption puts them more in line with those of the other studies. In any case, it does mess things up a bit. LSD being a phenethylamine/tryptamine hybrid may speak more to the parsimony of plant and fungal biochemistry than to the relation of phenethylamine to tryptamine SARs. Makes for a bit of a jarring disconnect in our levels of description, going from the atomic to the behavioural. I guess it at least gives rise to a couple of predictions, like that a 4-sub-5-MeO tryptamine should be active, mimicking LSD better than 4- or 5-sub tryptamines alone.

 

[DotChem]

Ketamphetamine

 

[white55]

4-ho/aco (and 4-po ones are even harder) tryptamines are harder to make than 5-meo or unsubstituted (naked?) ones so that the 4-ho/aco version wasn't made wouldn't be a huge surprise. 5-meo-dalt is/was around for a long time but 4-aco-dalt was only made in small amounts despite being better (not that being better than 5-meo-dalt is a huge achievement since 5-meo-dalt is trash) .....

 

[SKL]

IME acetoxy esters and asymmetrical tryptamines are almost always better but obviously harder to make for what is already a boutique market at best. Too bad. 4-AcO-MiPT was a beaut but barely circulated.

 

[Dresden]

Was it much different from 4-OH-MIPT? I quite enjoyed a heroic dose of that.

 

[SKL]

I am not quite sure that I did both enough times to give anything approaching and "objective" answer, but as far as I can speak to it the acetoxy was in fact better; smoother in body, slightly less tension both in the muscles around the upper body, the sternocleoniomastoid and trapezius in particular which is where this sort of tension from psychedelics tends to strike me, mentally a bit less jumpy yet more hallucinogenic in a superficial sense, about equally mentally and intellectualy. This is more or less the same as the differences between 4-AcO- and -HO-DMT and may of course have been placebo-influenced and colored by my considerably larger experiences with those (including synthetic psilocin.) I do think the ester makes a worthwhile difference …

Speaking of has anyone ever tried pure/synthetic 4-PO-DMT or any 4-PO-T's? I've certainly never seen or tasted them or known then to circulate though I'm sure someone has made them.

 

[white55]

Other than in clinical studies? Should be extremely unlikely as it was not that long ago that the only know synthesis was very dangerous (as in goes boom quite easily). A safer one was then developed by one of the chemists working for Nichols but it's probably still much more expensive for rc vendors..... the fact that the leading theory was that the active compound was the 4-ho version and that any esters get removed and are inactive probably didn't help.

 

[Dresden]

This is indolylic fentanyl.

 

[DotChem]

^ Fentadol? Indotanyl?

 

[Dresden]

Doltanyl

 

[EP-11]

 

[aced126]

Quite a silly creation which I'm not gonna bother naming. I had an idea that this adamantane-guanidine fragment could function as a sort of "fat and bulky amine". Unfortunately this molecule seems to be very unstable.

 

[DotChem]

Benzovalerone .. aka Pyrozepam ..