Is it possible that there are base tryptamine equivalents in the lysergamide family?

[Hilopsilo]

Was thinking about this the other day, you can have these short lived extremely powerful experiences with the base tryptamines, but nothing like this exists in the lysergamide family. Based off chemistry knowledge alone, could one hypothesize whether it is possible for a lysergamide "DMT-equivalent" to exist? Even if undiscovered at this point. Essentially a substance that you could vaporize and it would produce an experience on the same level as DMT, but with the lysergamide flavor to it.

 

[Hodor]

I strongly dislike the term "base tryptamines" for non-ring-substituted tryptamines. Yes, I know people on Reddit like to use it, but it is still highly misleading.

At any rate, it's hard to say whether it would be possible to make a drug with a DMT-like intensity of effects and a "lysergamide flavor" when there isn't even an agreed-upon definition of what that "lysergamide flavor" entails. Even LSD-25, ETH-LAD, AL-LAD, LSZ and MIPLA, despite being very closely related in terms of their structures, tend to produce noticeable differences in terms of headspace, visuals, and bodyload.

 

[perpetualdawn]

Talking just structurally, I think the lysergamide analogy to the tryptamine drugs like DMT, DPT, MET (and so on) would be the tricyclic tryptamines. So drugs like NDTDI and RU-28306. Unfortunately these seem to have been non-promising so far.

 

[Hilopsilo]

I strongly dislike the term "base tryptamines" for non-ring-substituted tryptamines. Yes, I know people on Reddit like to use it, but it is still highly misleading.

At any rate, it's hard to say whether it would be possible to make a drug with a DMT-like intensity of effects and a "lysergamide flavor" when there isn't even an agreed-upon definition of what that "lysergamide flavor" entails. Even LSD-25, ETH-LAD, AL-LAD, LSZ and MIPLA, despite being very closely related in terms of their structures, tend to produce noticeable differences in terms of headspace, visuals, and bodyload.

Fair enough, i just read the term on psychowiki, wasn't sure what else to call the blank-blank_T tryptamines that blast you off in such a way. What would you call them? DMT, DPT, MET, DET, MIPT, etc.

Sure they vary, but so do all tryptamines, but its definitely apparent that dmt is similar to tryptamines than "lysergamides", the acid, idk what to call them. mushrooms is to DMT as LSD is to ______, what would it be? is there any reason to believe it might exist?

 

[cj187]

I agree about "base tryptamines" being misleading. I prefer the term "simple tryptamines."

Structurally, there isn't really a DMT equivalent of LSD. It's not impossible that somebody could discover something related to LSD that's as powerful as DMT, but I wouldn't count on it. A lot of LSD analogs have been tested and they tend to be less psychedelic than LSD. There has been speculation that 12-MeO-LSD could be a more powerful LSD, as it's structurally analogous to 5-MeO-DMT.

Maybe DPT is what you're looking for. Some people say that DPT is to LSD what DMT is to mushrooms. I don't exactly agree with that description, but in some ways it is a little LSD-like.

 

[Beenhead]

You are talking about N,N-substituted Tryptamines.

Since the 5ht agonism is built off the indole skelton, it seems the bulkier you make it, the more promiscuous it becomes and the effects become more varied compared to the traditional smaller psychedelics.

The instability of the Lysergamides also do not make them good candidates at all for vaporization.

 

[Hodor]

Since the 5ht agonism is built off the indole skelton, it seems the bulkier you make it, the more promiscuous it becomes and the effects become more varied compared to the traditional smaller psychedelics.

Based merely on its affinity for most receptors, LSD should not be psychoactive at doses of 100 micrograms. The Ki value for LSD at the 5HT2a receptor is roughly 2.9nM, an order of magnitude higher than for example DOI, meaning its affinity is around an order of magnitude lower (remember: the lower the Ki, the more tightly it binds). In other words, it should be DOI that is 10 times as strong as LSD, not the other way round.

However, current research based on x-ray crystallography methods suggests that the secret to LSD's extremely potency lies in the way it essentially gets "stuck" in the receptor once bound (as opposed to other psychedelics, which constantly bind to and dissociate from receptors).
https://phys.org/news/2017-01-lsd-brain-cell-serotonin-receptor.html

I also do not think that LSD's "promiscuous" affinity for various dopaminergic and adrenergic receptors actually contributes to the "flavor" of its psychedelic experience. The affinities for these are in the tens of even hundreds of nanomoles, so unless LSD has a similar mechanism for getting trapped in those too, it is pretty safe to say that 100 micrograms would be far too low of a dose to elicit any sort of effect via direct agonism at these receptors.
Remember, however, that not all forms of 5ht2a agonism are identical. One agonist may activate different effector pathways than another. The lethality of NBOMe overdoses, for example, is now attributed to their ability to activate signalling pathways involved in blood coagulation, which, when combined with major vasoconstriction, could cause death by cardiac ischemia.

 

[perpetualdawn]

Holy shit that was super interesting Hodor.

From that article you linked to:

Eventually, though, an acid trip ends. Some LSD molecules pop off their receptors as the lid moves around. Also, brain cells eventually respond to this strange molecule by sucking the receptor into the cell, where it - along with the LSD—is degraded or disassembled for recycling.

I wonder if this "sucking the receptors" is the mechanism behind downregulation/tolerance. Perhaps it would explain why DMT apparently doesn't cause any tolerance build up - the drug washes out of the receptor so fast that the neurons don't get around to sucking up these receptors, so no tolerance.

Really fascinating that we're getting a more detailed view of how these drugs work.

 

[Hodor]

I wonder if this "sucking the receptors" is the mechanism behind downregulation/tolerance.

More or less, yes. There are complex feedback mechanisms in place to prevent receptors from being constantly activated. These include making it harder for the receptor to pass on its signal by attaching phosphate residues to it, or attaching certain proteins ("arrestins") that can shut it down full stop, under the assumption that the receptor is defective and needs to be broken down and replaced.

This process seems to happen significantly faster with irreversible or ultra-high-affinity agonists, and LSD (due to its propensity for getting "trapped" in the receptor for hours) could effectively be considered a pseudo-irreversible agonist.

 

[Beenhead]

Based merely on its affinity for most receptors, LSD should not be psychoactive at doses of 100 micrograms. The Ki value for LSD at the 5HT2a receptor is roughly 2.9nM, an order of magnitude higher than for example DOI, meaning its affinity is around an order of magnitude lower (remember: the lower the Ki, the more tightly it binds). In other words, it should be DOI that is 10 times as strong as LSD, not the other way round.

However, current research based on x-ray crystallography methods suggests that the secret to LSD's extremely potency lies in the way it essentially gets "stuck" in the receptor once bound (as opposed to other psychedelics, which constantly bind to and dissociate from receptors).
https://phys.org/news/2017-01-lsd-brain-cell-serotonin-receptor.html

I also do not think that LSD's "promiscuous" affinity for various dopaminergic and adrenergic receptors actually contributes to the "flavor" of its psychedelic experience. The affinities for these are in the tens of even hundreds of nanomoles, so unless LSD has a similar mechanism for getting trapped in those too, it is pretty safe to say that 100 micrograms would be far too low of a dose to elicit any sort of effect via direct agonism at these receptors.
Remember, however, that not all forms of 5ht2a agonism are identical. One agonist may activate different effector pathways than another. The lethality of NBOMe overdoses, for example, is now attributed to their ability to activate signalling pathways involved in blood coagulation, which, when combined with major vasoconstriction, could cause death by cardiac ischemia.

Very interesting, yes 5ht agomism is for sure not created equal, as there are serotonin receptors outside the brain.

The case if DOI vs LSD is one reason why we cannot fully explain the subjective effects of a drug purely off in vitro assays.
I once made a column with microtubules and tau, trying to look at phospho patterns and different kinases phosphorylated sites they probably couldnt in vivo because the sterics were different

LSD does seem to be an absolute perfect fit for the 2a if I remember a paper that came out several years ago.

A question id like to posit for you, why do you suppose, if LSDs promiscuity for other receptors is not effectual, causes the sharp difference in subjective feeling between the N subbed tryptamines and the Lysergamides?
The former feeling slightly edgy while the latter having that clean stimulating quality?

 

[atara]

Who says [freebase] LSD can't be vaporized? For all we know, that's the most plausible actual explanation for Bicycle Day.

 

[Hodor]

Who says [freebase] LSD can't be vaporized? For all we know, that's the most plausible actual explanation for Bicycle Day.

Bicycle day was when Hofmann first *intentionally* ingested LSD in 1943, for which he used the oral ROA.

If you're referring to Hofmann's initial (accidental) ingestion of LSD in 1938, the most plausible explanation is that he simply got traces of LSD into his mouth or eyes by accident.

It wouldn't be the first time for a substance to be serendipitously discovered like this - for example, a number of artificial sweeteners were discovered by chemists getting some of the material onto their fingertips (or, in case of cyclamate, a cigarette) immediately noticing the taste when they later inserted them in their mouth.

 

[perpetualdawn]

Is it likely that psycehdelic molecules other than LSD and the lysergamides also have this property of getting "strapped in" to the 5ht receptor to varying degrees, or does it seem like this story is more of a property that's specific to the shape of lysergamides?

I wonder if the nbomes' long shape means that they too get stuck in the receptor like LSD. It might explain their extreme jump in potency compared to their cousin 2C-x.

I also wonder if drugs that don't get stuck in the receptor, aside from the really quick ones like DMT, will also induce less tolerance, because of less of this receptor "sucking in" (to use the technical term lol ;D ). I've noticed that 2C-D for example doesn't seem to build up much tolerance, but I don't usually push the doses either.

Was the above study looking at 5ht2a specifically, or serotonin receptors in general?

 

[Beenhead]

Looking at the 2 dimensional line drawing of a molecule can be a very misleading representation of its actual shape in 3 dimensions.

The size of the atoms and their steric locations on the carbon chains play a huge role. Its also the location of electronegative atoms, electron donors/acceptors, and non-polar regions of the molecule in space that determine the binding characteristics for a receptor or enzyme.

In an active site, you will have certain residues (amino acid side chains) that a necessary for binding and they must have an affinity to certain regions of the molecule being bound.

Here is an example from Roth 2017, Cell.

The diethylamine chain of LSD is absolutely essential in understanding its ability to bind to the active site of thw 5ht2a and b receptor

The diethylamine chain creates an interaction where the the receptor/ligand complex forms a ridgid structure where other conformAtional changes are slow to occur, as LSDs on/off rate is very slow.
This is partly explained by the interaction of the side chain with residue Lysine-209. This interaction creates a sort of ?cap? that seals the active site, which holds LSD and thereby the conformation of the receptor in place. By making a substitution at that residue L209A (Lysine to Alanine)that does not allow this interaction, the on/off rate is increased and B-Arrestin signalling is slowed.

Lysergic Acid does not have the diethylamide side chain and cannot form this complex with the cap, which is supposedly why its much less potent.

Much of this work was peformed with x-ray crystallography, and molecular mechanics calculations.
I suspect there could be some very interesting studies with HDX Mass Spec in this field.

 

[HOOH]

Based merely on its affinity for most receptors, LSD should not be psychoactive at doses of 100 micrograms. The Ki value for LSD at the 5HT2a receptor is roughly 2.9nM, an order of magnitude higher than for example DOI, meaning its affinity is around an order of magnitude lower (remember: the lower the Ki, the more tightly it binds). In other words, it should be DOI that is 10 times as strong as LSD, not the other way round.

However, current research based on x-ray crystallography methods suggests that the secret to LSD's extremely potency lies in the way it essentially gets "stuck" in the receptor once bound (as opposed to other psychedelics, which constantly bind to and dissociate from receptors).

resurrecting this thread from the depths of hell to ask more about this either from you or anyone knowledgeable: how can it be the case that LSD has a relatively high Ki if it literally gets stuck inside the receptor, thus having no means of dissociating from it.

 

[HOOH]

Lysergic Acid does not have the diethylamide side chain and cannot form this complex with the cap, which is supposedly why its much less potent.

Is there anything indicating lysergic acid to be active? This is a common thing I see I in older literature, even Huxley seemed to refer to LSD as "lysergic acid", but I don't think it would be active and this is just an attempt at simplifying "lysergic acid diethylamide" and consequently failing at a chemical level.