Acid, dragonflies and the 5HT2A receptor

[dread]

Making the 6-nitrogen a secondary amine destroys activity. Also that extra double bond... I don't know, man.

I would rather do it like this:

 

[/navarone/]

^ 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.

Well Bromo-DragonFLY has an extraordinary high acivity for 5-HT2 receptors and so does LSD.

The reason why Bromo-(fully aromatic)DragonFLY is more potent is because of the ether aromatic ring wich gives more stability to the oxygen molecule that would bind to the top hydrogen donor.

The reason why i switched the 6- nitrogen with an oxygen is because it has a double lone pair electron rather than a single one found in nitrogen (also 6-alkylated nitrogen indoles decrease activity by 1/10th or more, this suggest that the lone pair is very important for lower H binding activity).
This might increase the lower H binding affinity

Both LSD and X-DragonFly fit perfectly in the 5-HT2 receptor, why wouldn't this molecule behave the same way? do u think that it too bulky to fit in?

And (according to the main post by the great F&B, the greater the lipophobic activity the stronger is th activity of the molecule, then why switch Iodine with Bromine?

In fact i dont understand why 2-CB is prefered to 2-CI. Could someone explain this please?

Honestly, I have no information regarding the double bond i added on the cyclohexane ring next to the idole group but since most of the common potent tryptamines (DMT, Bufotenin, 5-MeO-DMT, psylocin ect..) have a planar ethanamine group stucture.
By adding a double bond the molecule, it would have a more planar structure and possibly a higher potency.

 

[dread]

You switched the 1-nitrogen with oxygen. You are confusing nitrogens 1 and 6 here.

You left the 6-nitrogen a secondary amine, which destroys activity. About the 1-nitrogen changed to oxygen, that might work or it might not. Apparently it works on some tryptamines.

I changed the aromatic furan group to a simple methoxy group, because this way it resembles more like serotonin. Also that methoxy group is the same as the 5-MeO-group in 5-Meo-tryptamines, which increases activity.

About bromine instead of iodine, well, everyone says they enjoy the effects of DOB more than DOI. It's not all about potency you know.

About the double bond. This would take away one of the chiral centers. This chiral center is probably important, because changing the chirality of that center again destroys activity. Also I have never heard of tryptamines with a double bond in the ethyl chain, or phens with a methylene group attached to the alpha carbon.

 

[nuke]

Considering you lose most activity if you even drop a carbon from the nitrogen on the amide and the compound has only one out of four enantiomers active, I really doubt the activity of a lot of these crazy hybrid molecules. The binding of LSD is very, very particular.

 

[dread]

There are however some substitutions you can make that retain or even increase activity.

For example, the dimethylazetidide in place of the amide, or the 6-ethyl or 6-allyl in place of 6-methyl... all of those increase the activity.

 

[/navarone/]

Ehmm.. what?

EHmm...What?

Azetidide

N-Dimethylazetidide is a quaternary ammonium compound.
No offence but, I think you got a little confused unless your talking of 1,2/2,3/1,3-dimetyl azetidide

 

[vecktor]

in dimethyl azetidine the methyls can be located on the carbons or a carbons and the nitogen there are 5 isomers that I can see, and only N,N-dimethylazetidine is a quaternary compound.

I don't really like the use of azetidide to denote an amide derived from azetidine, but it is proper because, morpholide and piperide are used to refer to mophline and piperidine.

navarone, you might want to look into 14 methoxy LSD and 13 methoxy LSD before designing ergolines with substitution at those positions.

the other significant point is just because the two molecules can overlay in a model to a extent this does not mean they interact and bind to the receptor in the same way, or even that they activate the receptor in the same way.

this thread reminds me a lot of the threads helios used to post here fortunately he had telepathic drug assay techniques.

 

[Hammilton]

Ilostamadge made good use of telepathic assaying.

 

[UnfortunateSquid]

The azetidine LSD derivative which is being spoken of is LSD, but with the diethylamine moiety replaced with a 2,4-dimethylazetidine moiety.

This locks the ethyl groups of LSD in the "gullwing" conformation, thought to be the most active conformer (in a similar way to dragonflies locking the lone pairs of the oxygen atoms in their active conformation).

This of course results in 2 new chiral centres, and a number of isomers. One or two of these (I think there are 3? I just ate some mcdonalds [a rare indulgance] and feel quite ill, so cannot be bothered working it out) are more potent than LSD itself, as far as 5ht-2a affinity goes, anyway.

Nichols did the paper, it's referenced somewhere round here (probably in this thread). I'd UTFSE, but seemingly nobody else could be bothered to so why should I?

See aforementioned McD's comment. That shit should be banned, never mind acid.

 

[nuke]

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...

It's well mapped structurally actually, at least in terms of the binding of phenethylamines and various antagonists, refer to Nichols' "Serotonin Receptors" review published a couple years ago as well as Glennon's most recent papers. Especially interesting is the Nichols' paper where he looks at the binding of (S)-DOM vs. (R)-DOM. I do have a sequence of it, it's easily applied to the recently published human β2-adrenergic G protein–coupled receptor. There's still some confusion about the binding of tryptamines though.

 

[surrеalist]

Well there are various papers out there that show that 5-HT2A mediated behaviour is reduced by 5-HT1A agonists, headtwitch being blocked by 8-OH-DPAT. (Though I suppose you could argue that head-twitch isn't correlative with hallucinations)

How could pindolol potentiate DMT by partial agonist activity, when DMT is a full agonist at 5-HT1A with a very similar affinity as to 5-HT2A?

Also, why would psilocin be about half as potent as DOM in man, even though their 5-HT2A affinities are very similar, when psilocin is a good 5-HT1A agonist, and DOM has no activity there? (I suppose one could argue pharmacokinetics?)

And finally, Lisuride: 5-HT1A and 5-HT2A agonist, but it has an affinity about 10-20 times higher at 5-HT1A than 2A. And its completely lacking in hallucinogenic activity in humans. How does that fit in with your theory?

You guys seem to miss the point that LSD is a 5-HT1A antagonist. This is one of the many things that make it so special- it's ability to act both as a 5-HT2A agonist and a 5-HT1A antagonist. It has nearly equal affinities for both.

 

[(zonk)]

I think it's an agonist at every receptor aswell as an antagonist. All the lysergic compounds are. LSA is more antagonistic and methergine is even more antagonistic.

 

[Hammilton]

I think it's an agonist at every receptor aswell as an antagonist. All the lysergic compounds are. LSA is more antagonistic and methergine is even more antagonistic.

Were these sentences generated by machine? because they don't seem to make any sense at all.

It's an agonist at every receptor as well as an antagonist???? English maybe??

 

[surrеalist]

I think it is an antagonist at the presynaptic autoreceptor, and an agonist at the postsynaptic receptor (although technically I guess those are two different receptors).

I have also read that it is only a partial agonist, that it can bind to one receptor in two different orientations- one agonistic and one antagonistic.

 

[Hammilton]

Most ergoloids are partial agonists. LSD has about 25% efficacy vs. 5HT.