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Acid, dragonflies and the 5HT2A receptor

I was going to save a copy of this discussion for my personal reference when I noticed that a lot of the figures from the OP are missing. What happened?
 
Let's refresh the good old thread.

Is anybody out there who heard about furano-tryptamines?
Things like shulgin's inactive MDO-tryptamines with only one oxygen, either on 4- or the 5-position. From the 5-position there are two regioisomers possible: one tying the 5-membered ring from 5 to 4 and one from 5 to 6.
Is it possible that they are active or can one assume them inactive, when the MDO's are inactive?
 
^ The MDO-Trypts are not inactive that I am aware, though certainly have scant testing

notably 4,5-MDO-DIPT was in TiHKaL assay noted at 25mg after a 3hr post-consumption lull by this " I was reminded very much of LSD"
 
Some pictures

Thanks for the reply,

here are some of the pictures, I imagine.
I simply love to imagine new structures and there's still so much to investigate. What's your opinion. Could they fit into the pharmacophore model?
 

Attachments

fastandbulbous said:
Original figures/diagrams restored to article
Click to expand...

looking at figure 4 what would one hypothesize a b-methoxy-DOM would be dosed at?
perhaps 2-fold as potent? (bMeO-2CD is 2-fold as potent as 2CD in the figure)

this also goes back to my speculation in a recent thread that concerned potential more potent 'bk-MDMA' type structures to thwart UK laws to look at a beta-methoxy-MDMA (bMeO-MDMA or Methoxylone [first coined here and possibly first 'suppositioned', LOL] )

oh and nice on having those diagrams back..thanks Fnb! :)
 
C6H6 said:
I didn't mean to rule out that the above molecule will be active. What I meant to say is: there's only one way to find out if it is active as predicted: make it and test it. Since 3-chloropropionyl chloride is commercially available it would be an easy task to make this compound.

Another idea not related to this structure is to use the same rigid pyrrolidinylmethyl sidechain in PEAs which has proven to bring maximum potency to tryptamines:
attachment.php

The 4-OH-indole derivative is the most potent 'tryptamine', in rat drug discrimination equipotent with DOI and about 1/10 of LSD. It would be interesting to know how the activity of PEAs responds to this modification.
Click to expand...

did you ever find out more about this?
 
Going back to the issue of how altering the alkyl substitution of the amide group of LSD causes a big drop in potency, is there any info as to the activity of the amide of 2,5-dimethylpyrrolidine. It's that the azetadine amide (2,4-dimethylazetidine) is as active as LSD although I'm uncertain it has the same subjective feel as LSD (should be able to report back on that one sometime soon hopefully). The positioning of the carbon atoms should be similar to the 'gull wing' shape that the diethylamide assumes when bound to the receptor (hence why the azetidine derivative retains activity)
 
^^ Where are you getting information on the shape of the 5ht2a? I have searched the protein data banks and found nothing.

Actually, a protein sequence would kick ass, so I could just draw it! I promise Ill post any pictures I draw of this receptor here!
 
Unfortunately the AA sequence won't be very useful without knowing how it's "folded."

This said, there are some models of the receptor around. I know Longimanus and Erny were working on one (or rather two, I'm pretty sure they did so independently) and I'm pretty sure Nichols has one but I don't think it's been published.

I think you're referring to the part where FnB mentions the shape of the dimethylazetidine derivative. He's not talking about the shape of the receptor, but rather the conformation of the LSD derivative. This is at least something we can look at fairly easily with MM2 minimization using something like Chembiodraw 3D.
 
we can look at fairly easily with MM2 minimization using something like Chembiodraw 3D.


can we? (pix plz )
 
I realize what he is talking about, but How do you know the shape that the molecule will make with out knowing the shape of the active site. Are you saying the active site has been mapped?
Well I can throw up a pic of LSD with a MM2, but how do you know its conformation in the receptor? I have CHem 3d, so Ill draw it and put it up...
 
lsd.jpg
Diethylamine bondlength 1.5 ang

lspyrrolidine.jpg
Bond lengths in pyrrole all 1.5 Ang

lsazetiidine.jpg
Bond lengths in Azetidine 1.4-1.6 Ang.

These were all minimized with the MM2 function, though I think Gaussian or Mopac would of been better. The azetidine just looks so much smaller compared to even the pyrrol. Seems like any type of dipole/dipole or vander waals force going on is not going to be nearly as strong at that distance. No?

LSD and Its Lysergamide Cousins
David E. Nichols, Ph.D.*



The two ethyl groups were incorporated into ring
structures such as the pyrrolidide, piperidide, and morpholide,
shown above, but these also had reduced anti-serotonin and
psychedelic effects (Cerletti and Doepfner 1958). Although
the morpholide had less than one-tenth of the potency of
LSD in blocking the action of serotonin, it did however have
nearly 75% of the potency of LSD as a psychedelic
(Gogerty and Dille 1957)....


...We have recently been doing computer-based
modeling of the 5-HT2A receptor, based on the 3-
dimensional structure of bovine rhodopsin that was
published in August 2000 (Palczewski et al., 2000).
Rhodopsin has some similarity to brain amine
receptors, and current receptor modeling efforts are
based on that model. Our preliminary results indicate
that the diethylamide group binds within a small cavity
that is formed by amino acids located at the top of
transmembrane helices 2, 3, 6, and 7. The carbonyl
oxygen atom of the diethylamide group appears to form
hydrogen bonds to an asparagine residue near the top
of transmembrane helix 6 (J. Chambers and D. E.
Nichols, unpublished results). The space where the
diethylamide binds is bounded on all sides by amino
acids that make up the receptor itself. Placing a group
larger than a diethylamide into that cavity distorts the
receptor, and an alkyl group smaller than a diethylamide
causes the receptor to change from the shape it
adopts when a diethyl group binds, which presumably
is an optimum arrangement.
It will probably be a long time before we
understand how subtle changes in the shape of the
receptor, or small deformations in its structure, translate
into vast differences in activation or inhibition.
Translating these receptor effects into actions on
consciousness will take a whole lot longer!
I return now to the observation that Dr. Hofmann,
in discovering the effects of LSD, had gone back to
reexamine the 25th in his original series of lysergamides
five years after its original synthesis, because of a
“peculiar presentiment.” Based on what we know today
about the strict limitations on structural change that
can be accommodated in the lysergamides, and on the
constricted geometry of the receptor domain that binds
the diethylamide group of LSD, his desire to focus
attention on that one particular and unique compound
seems even more baffling!
Click to expand...

EDIT:

So it seems from this article that these rings are too small and distort the shape of the receptor, dropping affinity,a nd potentcy. Its amazing that LSD fits JUUUUST right to create the perfect fit..
 
Last edited:
Beenhead said:
I realize what he is talking about, but How do you know the shape that the molecule will make with out knowing the shape of the active site. Are you saying the active site has been mapped?
Well I can throw up a pic of LSD with a MM2, but how do you know its conformation in the receptor? I have CHem 3d, so Ill draw it and put it up...
Click to expand...

Because the compound prefers the energy minimized state (for obvious reasons), it will assume this state most often. For a drug that's so exceptionally potent, one can only assume that it's binding in a conformation equal to or very close to the minimized state.

And like I said, there are models available of the active site. It's hard to say how accurate they are, though.
 
Greetings everyone.

Unfortunately i'm really in a rush but after reading the post from F&B about %-HT receptor affinity, i couldn't keep myself from sketching a new molecule.

Its a hybrid between LSD-25 and Fully aromatic iodo-DragonFLY with an extra double bond on the cyclohexane ring to give the molecule a more planar structure.

I'll post a bitmap image right away:



5-ht receptor activity arent't my forte but any opinion would be greaty apreciated.
 
Some interesting information about LSD receptor affinity that i easey found on th net.

LSDaffinities.GIF


BTW could someone explain to me the meaning of that black line at the bottom of the graph?

Plus, could anyone share their opinion on the activity of the theoretical LSD-IodoDragonFLY hybrid I posted above?

Thanks
 
^ where is the chart from? the looks like a 10 nM cut off, why 10nM I don't know, but it is used I guess as a guide to which receptors it would interact with at I guess a typical physiological concentration.

IMHO the hybrid dragonfly ergoline is just an abomination, it fits neither the known SAR of ergolines at 5ht2a nor the SAR of the phenethylamine/ dragonflys. it is it doesn't fit the rule of 5 either. a waste of time.
 
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