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  • N&PD Moderators: Skorpio | someguyontheinternet

I Like to Draw Pictures of Random Molecules

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lol, Yeah, probably. Snorted mephentermine powder was damn close to amphetamine in effects, I know that much. How that translates to a beta-ketone with a 4-methyl would probably have to be assayed in vivo for us to know. But yeah, chances of it being close to mephedrone are slim, I guess. :)

I don't take stimulants or empathogens any more, so I don't really care. It was just a funny thought I had, and I thought I'd share it. I'd rather bet my money on this one being more worthwhile, than that mexedrone fail. (not that I've treid that one either, it's not my thing really)
 
I bet this has been drawn before, but does anyone know if open chain LSD analogues have been evaluated?

N-methyl-N-(2-(N%2CN-diethyl)amino-2-oxoethyl)tryptamine.png
 
The phenethylamine/amphetamine open chain compounds have been investigated: they have effects on blood pressure but aren't hallucinogenic.

CjoELTK.png
 
Yeah. How about something like this? Could be interesting. Would it be easier to synth than LSD?

LSDana_zpsvnr0ue1o.jpg
 
aced126 said:
I bet this has been drawn before, but does anyone know if open chain LSD analogues have been evaluated?

N-methyl-N-(2-(N%2CN-diethyl)amino-2-oxoethyl)tryptamine.png
Click to expand...

If you're trying to increase potency I think it's a better bet to mess around with constraining the basic tryptamine amide ala 4-ho-mpmi and/or indazole substitutions in lieu of indole

pretty sure the pocket of 5ht2a that LSD's diethylamide docks in is rather unreasonable to try and reach with an open chain (would be just too floppy)

I'd really like to know what the rationale was that led to the discovery of 4-HO-MPMI cause it sure would be enlightening!
 
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Midnight Sun said:
If you're trying to increase potency I think it's a better bet to mess around with constraining the basic tryptamine amide ala 4-ho-mpmi and/or indazole substitutions in lieu of indole

pretty sure the pocket of 5ht2a that LSD's diethylamide docks in is rather unreasonable to try and reach with an open chain (would be just too floppy)

I'd really like to know what the rationale was that led to the discovery of 4-HO-MPMI cause it sure would be enlightening!
Click to expand...

I wasn't really trying to improve potency. In fact the reason why LSD is so potent itself is probably because it is in a rigidified conformation.

Idk, dimethyl > pyrrolidine is a pretty obvious modification lol; I'm sure they synthesised molecules with much more complex modifications.
 
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sekio said:
The phenethylamine/amphetamine open chain compounds have been investigated: they have effects on blood pressure but aren't hallucinogenic.

CjoELTK.png
Click to expand...

I think conformal rigidity might be an issue. The alkyls on the amide appear to be required for space-filling since some secondary amides also work. It's that N lone-pair that is the important bit. The NBOMe class overlays the O of the benzyl-methyl ether so I would look at the directions of the lone-pairs. Just a thought - I could be miles out.
 
Yeah but with the NBOMe class, IIRC even 25-NBOMe - the 2C-H analogue - is apparently just nasty and adrenergic let alone free phenyl or mono/dimethoxyphenyls (in terms to tolerating less substitution on the ring). Hans Meyer in PD is testing NDEPA compounds on himself that are based on more classical psychedelic PEAs with often a 2,4,5 substitution pattern. They apparently DO work, anecdotally.

Without a fully constrained lysergamide structure nor such a phenyl substitution pattern on a non-constrained open chain compound you are apparently missing too many binding sites incl. on both ends, for the molecule to both fit on the receptor AND activate it by doing something to the conformation of the receptor protein. An uncanny likeness on one side of the molecule but not the other just makes the above structures remote meth / stim neurotransmitter cousins that apparently are generic enough to do the job as a sympathomimetic drug.
 
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Right then, new idea: what would happen if the indole was replaced with a benzene, like so:
hexahydro-4-methyl-2-(1-oxo-(N%2CN-diethyl)aminomethyl)-4-benzoquinoline.png


Look at the image for reference:
gsTjhiH.png
 
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Dunno if it would be active as a hallucinogen, the 9,10 double bond is needed for psychedelic activity

TP2Pwtd.png


But it's been made though, refs
Horii et al. Chemical and Pharmaceutical Bulletin, 1966 , vol. 14, p. 1227-1234
Bulletin de la Societe Chimique de France, 1968 , p. 4463

Apparently it has oxytocic activity, so presumably it hits some of the serotonin receptors ?
 
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sekio said:
Dunno if it would be active as a hallucinogen, the 9,10 double bond is needed for psychedelic activity

TP2Pwtd.png


But it's been made though, refs
Horii et al. Chemical and Pharmaceutical Bulletin, 1966 , vol. 14, p. 1227-1234
Bulletin de la Societe Chimique de France, 1968 , p. 4463

Apparently it has oxytocic activity, so presumably it hits some of the serotonin receptors ?
Click to expand...

I meant to have the double bond there, but I couldn't manage to find a way to name it on Opsin. I have a feeling removal of the indole system will still retain activity to an extent.

Anyway, if the double bond is needed for activity, what does that say about how the molecule interacts with the pocket? Even a small conformational change results in a massive drop in potency, implying that the rigid structure which LSD takes is crucial to not only binding to, but also activating it. Yet however other 5HT2a agonists which have a similar backbone to LSD (like DMT for example) are very active of course, only at 2 or 3 orders of magnitude higher. With that being said, would dihydro-LSD and lumi-LSD be active when administered in much higher doses?

On to a different question, is there a structural link I am missing between the 2C-X series and tryptamine series as they both hit the same receptors.
 
The C=C is necessary to maintain the planarity of the LSD molecule. Without that planarity, it is inactive. But that doesn't mean that your molecule won't be active, just probably not as a psychedelic. So yeah, basically what sekio said.
 
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