Thoughts on LSD chemistry

[entheogenic-gnosis]

In a recorded lecture by David E. Nichols (

) he demonstrates how there is a molecule of tryptamine burried with in the structure of LSD, if you follow the two carbon bridge up from the indole ring you come to a nitrogen atom (position 6) with a methyl (ch3) group attatched. It seems to me that there is a molecule of N-methyltryptamine (NMT ; Mono-methyl-tryptamine) burried within the LSD molecule. Which leads to my question

Would it be possible to add another methyl group to the nitrogen at position 6?

(I know that if the DMT molecule was burried with in the LSD molecule the subjective effects would likley be similar to ETH-LAD, but it would be a novel combination in chemical structures)

This is just an idea off the top of my head, and I'm sure there's many flaws with it, I figured that if putting a dimethyl group on the nitrogen at position 6 of lysergic acid diethylamide was a good idea Hoffman or Nichols would have done it already, but seeing a structure so similar to DMT with in LSD, ive always wondered why nobody ever tried this before.

-EG

 

[Ufostrahlen]

I can't answer your question, but this video is really a highlight and way too short. I recommend watching it, since afterwards one will be much smarter.

If they could only fix the audio on the Neuroscience of Psychedelics Workshop vids... :roll:

 

[benzyme]

In a recorded lecture by David E. Nichols (

) he demonstrates how there is a molecule of tryptamine burried with in the structure of LSD, if you follow the two carbon bridge up from the indole ring you come to a nitrogen atom (position 6) with a methyl (ch3) group attatched. It seems to me that there is a molecule of N-methyltryptamine (NMT ; Mono-methyl-tryptamine) burried within the LSD molecule. Which leads to my question

Would it be possible to add another methyl group to the nitrogen at position 6?

(I know that if the DMT molecule was burried with in the LSD molecule the subjective effects would likley be similar to ETH-LAD, but it would be a novel combination in chemical structures)

This is just an idea off the top of my head, and I'm sure there's many flaws with it, I figured that if putting a dimethyl group on the nitrogen at position 6 of lysergic acid diethylamide was a good idea Hoffman or Nichols would have done it already, but seeing a structure so similar to DMT with in LSD, ive always wondered why nobody ever tried this before.

-EG

you wouldn't be able to add anything to that nitrogen: it's already covalently bound to three carbons, sharing all its valence electrons.

 

[Ufostrahlen]

you wouldn't be able to add anything to that nitrogen: it's already covalently bound to three carbons, sharing all its valence electrons.

Let's say you take AL-LAD and add an acetyl-group to position 1, like they did with LSD resulting in ALD-52. Or substitute ALD-52's methyl-group (6) with an allyl-group - an AL-ALD-52 so to say. Is that chemically (not pharmacologically) feasible?

 

[benzyme]

removing the methyl, no. replacing a hydrogen, yes.

now if there were an acetyl group bound, that would be a better leaving group...but i'd be concerned about epimerization. that would probably result in an inactive compound. it's best to start with an amine hydrogen.

 

[Ufostrahlen]

now if there were an acetyl group bound, that would be a better leaving group...but i'd be concerned about epimerization. that would probably result in an inactive compound. it's best to start with an amine hydrogen.

Ah okay, I understand. You think more of the reaction feasibility, I thought more of the end product soundness (which of course needs an synthesis route). I'm probably too naive here, I thought that more psychedelic ergoline-based substances should be known, since the known "psychedelic" groups (positions):

* diethylamide group constrained into an azetidine ring
* position 6 (eth, pro, bu, pargy, etc..)
* position 1 (acetyl)

should give plenty of combinations. But Nichols had certainly thought of that already.

 

[benzyme]

i'm thinking of ligand/receptor binding, and 3d orientation of the overall molecule... i.e. D-LSx is active, L-LSx is not.
creating the conditions for substitution reactions facilitates conversion from D to L.

 

[Ufostrahlen]

i'm thinking of ligand/receptor binding, and 3d orientation of the overall molecule... i.e. D-LSx is active, L-LSx is not.
creating the conditions for substitution reactions facilitates conversion from D to L.

I see - let me rephrase the question: do you see a condition for a (5R,8R)-1-Acetyl-6-allyl-N,N-diethyl-6-norlysergamide molecule to exist?

 

[benzyme]

as i was alluding to...it depends on what you're starting from. Ideally, it would be lysergic acid.

 

[entheogenic-gnosis]

you wouldn't be able to add anything to that nitrogen: it's already covalently bound to three carbons, sharing all its valence electrons.

Thank you benzyme! Now I can lay that idea to rest, I was wondering though if one were to start with Nor-LSD would it be possible to add a dimethyl group to the nitrogen at position 6?

There's a compound called 1,3,4,5-Tetrahydro-N,N-dimethylbenz[cd]indol-4-amine or "RU-28306", it was this compound that made me want to combine the chemical structures of LSD and DMT, then while watching that Nichols lecture I see a molecule of N-methyl-tryptamine already present in the LSD molecule, it would have been nice if it were possible to get two CH3 groups on that nitrogen at position 6....

But like I said many of these "off the top of my head" ideas are often flawed in some way, in this case the nitrogen I wanted to add something to was already "covalently bound to three carbon atoms, sharing all its valence electrons"

Thank you again for response I really appreciate it.:d

-EG

 

[Ufostrahlen]

as i was alluding to...it depends on what you're starting from. Ideally, it would be lysergic acid.

Thanks for clarifying this. Are you by chance aware of a freeware program, where one can create this particular molecule and test it against 5-HT & dopamine receptors?

 

[Nathanial.Dread]

as i was alluding to...it depends on what you're starting from. Ideally, it would be lysergic acid.

Thanks for clarifying this. Are you by chance aware of a freeware program, where one can create this particular molecule and test it against 5-HT & dopamine receptors?

Autodock and Autodock Vina are what we used in my Drug Design & Pharmacology Class.

Homepage

AutoDock Vina AutoDock Vina is an open-source program for doing molecular docking. It was originally designed and implemented by Dr. Oleg Trott in the Molecular Graphics Lab (now CCSB) at The Scripps Research Institute. The latest version is available here. AutoDock Vina is one of

vina.scripps.edu

The problem is, you need receptors that have been characterized by x-ray crystallography, and transmembrane proteins are very hard to crystallize. I'm not sure if the receptors we're interested in (D2, 5-HT2A, etc) have had their structures fully elucidated.

Blessings
~ND

 

[Ufostrahlen]

Autodock and Autodock Vina are what we used in my Drug Design & Pharmacology Class.

Homepage

AutoDock Vina AutoDock Vina is an open-source program for doing molecular docking. It was originally designed and implemented by Dr. Oleg Trott in the Molecular Graphics Lab (now CCSB) at The Scripps Research Institute. The latest version is available here. AutoDock Vina is one of

vina.scripps.edu

So Autodock it is... Well, this doesn't make my situation easier. I played around with it, but loading a 5HT2A receptor or designing a molecule wasn't successful. Let alone running docking simulations.

The problem is, you need receptors that have been characterized by x-ray crystallography, and transmembrane proteins are very hard to crystallize. I'm not sure if the receptors we're interested in (D2, 5-HT2A, etc) have had their structures fully elucidated.

As far as I know, most GPCR aren't characterized yet. I tried to use this model, but I failed converting the plain text into the .pdb format. Then I thought: oh, well, let's use the Protein Model Portal - PSI SBKB for some predictions. But then I couldn't load the predictions it into Autodock. After that I lost more or less interest... :lol:

My idea was: use predictions for all important LSD & R-LAD receptors (5HT2x, Dx), then run docking simulations with LSD, AL-LAD, ALD-52, ETH-LAD and Lisuride (as a non psychedelic ergoline for control) on them. If my proposed AL-LAD-52 molecule matches the affinity values of the aforementioned molecules (except Lisuride), then it should be active as well.

 

[entheogenic-gnosis]

i'm thinking of ligand/receptor binding, and 3d orientation of the overall molecule... i.e. D-LSx is active, L-LSx is not.
creating the conditions for substitution reactions facilitates conversion from D to L.

I see - let me rephrase the question: do you see a condition for a (5R,8R)-1-Acetyl-6-allyl-N,N-diethyl-6-norlysergamide molecule to exist?

It's interesting that I stumbled across this thread, as I have been doing a good deal of research on compounds very similar to what you are describing, only using a propionyl substitution at position one rather than an acetyl substitution.

Though I'm certain that if one were all to synthesize 1-acetyl-6-ethyl-6-nor-lysergic acid diethylamide, that it too would be a prodrug of ETH-LAD...

Technically, it seems you could add an acetyl or propionyl substitution to the nitrogen at position one of any one of the xxx-LAD series, and this grouping would become the needed NH grouping of the pyrrole ring in vivo...

Hmmm...I bet 1-propionyl-Lysergic acid 2,4-dimethylazetidide would be a prodrug of LSZ in the same manner, or 1-acetyl-Lysergic acid 2,4-dimethylazetidide...

-eg

 

[dragonrider]

Would it be possible to do create LSH-analogue's, simmilar to the mentioned LSD analogue's? So ETH-LSH, Al-LSH, acetyl-LSH, etc.?

Another, more interesting question is: would it be possible to create LSA-analogue's like ETH-LSA, acetyl-LSA?
The reason why this would be more interesting is that LSA is realy different from LSD, and i have good reasons to believe that it actually counteracts some of the effects of LSD.

But the thing is: the effects of LSA are too weak in relation to it's side-effects, to make LSA a realy interesting compound from a psychonautic perspective. If you could create a compound that would have the effects of LSA, but with less side-effects, that could maybe be a whole new kind of psychedelic.

I think LSA itself is actually a mild dissociative. I don't know if it's an NMDA-antagonist (could very well be if indeed it's effects are pharmacologically the exact opposite of the effects of LSD), but i think the subjective effects of LSA are closer to those of NMDA-antagonists like ketamine, than to LSD. I don't think there's realy something like an LSA-hole, as it's way too mild for that. But there's some serious dissociation there for sure.
So it definately would be interesting to see if the LSA molecule could be manipulated in such a way that the subjective effects would be enhanced, while the physical effects would remain more or less the same. Acetylation could maybe do that? It works with aspirin and heroin anyway.

 

[downwardsfromzero]

^That's a representation of a 1-P ETH-LAD molecule. Just a methylene group away from 1-P ETH-LAZ.

Back to the original question, that ergoline 6-nitrogen could have an addition methyl group added. This would form a quaternary ammonium ion, giving the whole molecule a positive charge. The methylation reaction would be best carried out on a 1-acylated derivative of the molecule to prevent methylation of the 1-position.

I'd chuck some animations in but that program (Avogadro) is currently broken on the machine I'm using here.

 

[benzyme]

haven't used avogadro in years, but I remember it crashing a lot. I always liked Sybyl and Discovery Studio. and Pymol.

 

[nexalizer]

.. is this how people feel when I ramble on about computer networks & advanced security?

:d

 

[entheogenic-gnosis]

I quickly drew a depiction of LSD-25 with the NMT moiety highlighted in yellow (molecule "a" )

Then next to it, I depicted my concept compound from the initial post, where by adding an additional methyl group to nitrogen 6, (which apparently won't work anyway) you would be creating a LSD molecule with the DMT moiety burried within it, in effect, a DMT/LSD combination...

However, as was pointed out before

you wouldn't be able to add anything to that nitrogen: it's already covalently bound to three carbons, sharing all its valence electrons.

There is a compound called "RU-28306" or "N,N-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-4-amine" which can either be viewed as a cyclized version of DMT where the alpha carbon is joined to an additional carbon off position 4, causing a ring structure, or it could be viewed as a "simplified" version of LSD where "ring d" has been torn off the molecule...

As far as a DMT/LSD combination molecule, RU-28306 is likely the best bet...

-eg

 

[downwardsfromzero]

haven't used avogadro in years, but I remember it crashing a lot. I always liked Sybyl and Discovery Studio. and Pymol.

I've been quite pleased with the results from avogadro on the machine where it does work, although it was a bit crash-prone when pushed too hard. Doesn't look there's been much development work on it lately, either. Are the others you mentioned FOSS? Strictly zero-budget here at the moment.

EG, while the molecule you suggest is intriguing, it would be a quaternary ammonium ion and would likely have a very different pharmacology from LSD itself. Think aeruginascin vs. psilocybin.

It's the DMT structure that is buried within LSD as the nitrogen atom concerned is already joined to 3 carbon atoms, just as it is in DMT. For NMT you'd have to look at 6-nor-LSD.