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N-benzyl phenethylamines

dorothyperkins

dorothyperkins

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Oct 18, 2007
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While wondering what the effects of 5ht2c agonism are i saw this on wikipedia under 5ht2a receptor:

http://molpharm.aspetjournals.org/cgi/reprint/mol.106.028720v1

Apparently N-(2-MeO-benzyl)-2CB is a super potent 5ht2a agonist! I've never heard of it, anyone else? Does it seem to work as a psychedelic, in rats or whatever?

Interestingly the amphetamines became less potent and 2ci became more potent but less so than 2cb.

Edit: oh, refluxer mentioned them in the benzazepine thread!
 
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They might well be super-agonists at 5-HT2A but will they be psychedelics? Lisuride is a potent 5-HT2A agonist but produces no psychedelic effects. This has something to do with Gi/o proteins and Src. -2A agonists all stimulate PLC-b, and inhibition of PLC-b blocks psychedelic activity. Only psychedelic -2A agonists seem to stimulate the Gi/o and Src pathways.
All -2A agonists seem to induce the transcription of genes egr-1 and egr-2 but only psychedelic -2A agonists induce c-fos. It seems you need the concurrent activation of a couple of different things to get psychedelic activity (PLC-b + Gi/o + Src, downstream effect on: egr-1 + erg-2 + c-fos), and this arises from a particular conformation.

So, there must be a distinct receptor conformation that produces psychedelic effects through activation of several different pathways to produce a particular signalling signature. Unfortunately i'm not aware of any human bioassays of these compounds, nor testing of the above type (gene induction, G protein activation) with these N-benzyl agonists.

Look to these papers for more info, i'd write more now but i'm not in the mood right now..
Molecular Interaction of Serotonin 5-HT2A Receptor Residues Phe339(6.51) and Phe340(6.52) with Superpotent N-Benzyl Phenethylamine Agonists
Mol Pharmacol 70:1956–1964, 2006

Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior
Neuron 53, 439–452, February 1, 2007

There's a great paper I have on these too but it's in German, haha. (i don't read German, but you can still get a lot of useful data out of it) ... I don't know where it camne from though, there's no journal name on it etc from what I can see. Mystery! It's named "3 Pharmakologischer Teil" and the pages number 137 to 170.
 
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Yeah, someone does need to. Seems odd that no-one's made it and bioassayed it as it's so easy to make for anyone with access to 2C-B (2-MeO-benzyl chloride, or reductive amination with 2-MeO-benzaldehyde...)! Om nom nom nom ;) .
 
I have 5.5 years of german, I could probably translate it. Not sure how well I'd do, though. Can't say I focused much on pharmacology when I was there.
 
N-benzyl-5-methoxytryptamine appeared for sale as an RC a few years back after it was reported to have high affinity for 5HT2A, but it was soon discovered to be a 5HT2A antagonist rather than an agonist.

That german paper is interesting though, from what I could work out it did look like those N-benzyl phenethylamines he made were agonists, but my german isn't good enough to read it properly!

I would have thought someone must have tried these compounds already, surely it wouldn't be that hard to make N-benzyl 2CB for instance...but maybe everyone has always just assumed them to be inactive and missed out on a potential whole new family of valuable drugs.

The N-(4-bromobenzyl) and N-(2-methoxybenzyl) analogues also seem to have high affinity for 5HT2A, but again I'm not sure whether it has been established that they are actually agonists. Does make me wonder if the binding site has some symmetry though, maybe the whole 2,5-dimethoxy-4-bromo substitution pattern could be used at both ends of the molecule...wouldn't be that surprising, there are a bunch of opiate compounds that are basically two modified morphine molecules joined together by a bridge at the 6-position, and similarly dimers of GHB have been found to be much more potent GABA-B agonists than GHB itself.
 
Really? I never knew that about the dimers. That's interesting. Not too surprising. Many things in nature are highly symetrical. Makes sense that our receptors would too.
 
the 2-MeO ones are agonists, not sure about the 4-br. anyone have an idea what the best one would be out of 2-MeO, 2-OH, 4-Br, 3,4-MDO?

even with 2,5-diMeO-4-Br-benzyl its not symmetrical. could be interesting to make it actually symmetrical by sticking another carbon in there (ie. n-phenethyl rather than n-benzyl)
 
I'm not so sure about the dimers seeing as that paper I noted has determined the N-benzyl moiety is binding with a distinct and seperate amino acid residue. Might be worth a shot though :) !
dorothy, i'll get some figures for the substitutions you mentioned.
 
I can't find data for 3,4-MD or 4-Br substitutions any any of the papers I have, but here's some for 2-HO-Bz and 2-MeO-Bz, and 2,3-MD-Bz (it was the closest to 3,4-MD, and it looks good too!) :

N-(2-hydroxy)benzyl-DOI (racemic)
r5-HT2A Ki racemic [125I]DOI: 0.12 (0.02) nM
r5-HT2A PI Hydrolysis EC50: 6.34 (0.18 ) nM
r5-HT2A PI Hydrolysis intrinsic activity: 71 (2) %
h5-HT2A Ki racemic [125I]DOI: 0.061 (0.012) nM
h5-HT2A PI Hydrolysis EC50: 0.19 (0.03) nM
h5-HT2A PI Hydrolysis intrinsic activity: 86 (5) %

N-(2-methoxy)benzyl-DOI (racemic)
r5-HT2A Ki racemic [125I]DOI: 0.087 (0.010) nM
r5-HT2A PI Hydrolysis EC50: 2.50 (0.55) nM
r5-HT2A PI Hydrolysis intrinsic activity: 78 (6) %
h5-HT2A Ki racemic [125I]DOI: 0.044 (0.006) nM
h5-HT2A PI Hydrolysis EC50: 0.44 (0.07) nM
h5-HT2A PI Hydrolysis intrinsic activity: 81 (4) %

N-(2,3-methylenedioxy)benzyl-DOI (racemic)
r5-HT2A Ki racemic [125I]DOI: 0.19 (0.02) nM
r5-HT2A PI Hydrolysis EC50: 8.2 (1.6) nM
r5-HT2A PI Hydrolysis intrinsic activity: 68 (7) %
h5-HT2A Ki racemic [125I]DOI: 0.049 (0.008 ) nM
h5-HT2A PI Hydrolysis EC50: 1.07 (0.20) nM
h5-HT2A PI Hydrolysis intrinsic activity: 72 (3) %

For comparison: d-LSD
h5-HT2A Ki racemic [125I]DOI: 0.40 (0.02) nM
h5-HT2A PI Hydrolysis EC50: 0.22 (0.04) nM
h5-HT2A PI Hydrolysis intrinsic activity: 84 (3) %

Reference: Mol Pharmacol 70:1956–1964, 2006

Hope this is of use, cuz it took ages to type out haha :p .
As you can see the featured compounds are agonists about the same strength as LSD (intrinsic activity) which is good, but all we really have is PI hydrolysis and DOI displacement figures. As with what I was saying earlier about them needing to induce the right conformation, this doesn't tell us whether they'll be psychedelic, but what it *does* tell us is if they are they're likely to be pretty damn good, haha :) .
 
Many things in nature are highly symetrical. Makes sense that our receptors would too.
Click to expand...

Not at the molecular level they aren't. Proteins are nearly always made exclusively from L-amino acids and if you think about it, when optical isomers exist of a drug, one generally has a higher affinity for a target receptor than the other.

Symmetry is important in biological things when it comes to things like choosing a mate as asymmetry indicates less than ideal genetic make up, but at the molecular level symmetry is the exception, not the norm
 
Thanks Matt, though you could've just said the 2-MeO-benzyl one! I wasn't sure because some of the tables/columns in tables suggested otherwise. Still there doesn't seem to be a big difference between them.

Even if it's lacking psychedelic effects, would be interesting to see what effects triggering those other pathways has.
 
Oh dammit, you had the paper? Haha, I should read between the lines more. Ah well, at least now others can see the figures we're discussing. Yeah the 2-MeO one does look slightly better than the 2-OH one.
 
Yeah i posted it in the first post! Got pretty confused trying to figure it out though and wanted to make sure i wasn't misinterpreting it.

The 2-OH one is probably a bit tricky practically, being basic and acidic!
 
what about using N-benzyl to protect bk-PEA's ?

Anyone know if that would be sufficient to ensure stability?

I.e

bk-N-Benzyl-2C-B
 
Ham-milton said:
I have 5.5 years of german, I could probably translate it. Not sure how well I'd do, though. Can't say I focused much on pharmacology when I was there.
Click to expand...


i volunteer for German translations. It's my first language and i believe i can do a pretty solid job at translating it. For requests please write me a private message :)
 
Reminisant B: Yes it would prevent cyclisation, but it's not known if they are actually active yet. Don't use a unsubstituted ring though, the 2-MeO or 2-OH ones have way better affinity.
If these N-benzyl PEA's turn out to be active, then I expect the bk versions of them will be too, so long as that ketone doesn't throw a unexpected spanner into the works. I don't think i've heard of any bioassays or receptor affinity studies of bk psychedelic PEAs.

rave23: Ok i'll PM you later today, it'd be awesome if you could translate that german PDF :) .
 
^Interesting :)

Such simple solution could open a whole new avenue of otherwise impossible bk-PEAs
 
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