25B-NB (n-Benzyl-2C-B)

[MurphyClox]

Sorry if I may ask the obvious: What are you referring to with the term "simple dimethoxy"?

So, if you would consider NBOMe-TCB-2 *) to be a 'CW candidate', I assume that you think it's active... What about the Br-DragonFly-NBOMe-hybrid? I would expect it to be somewhat of a veeeeery slow onset but with hellish potency.

- Murphy

*) I assume we speak about this one:

 

[dread]

Does the cyclobutane analogue have any psychedelic activity? I thought it wasn't tested for anything except receptor binding...

Also the alphamethyl doesn't go well with the NBOMe...

So here's the bomb...

N-(2-methoxybenzyl)-2-[8-(trifluoromethyl)furo[2,3-f][1]benzofuran-4-yl]ethanamine

 

[MattPsy]

The mescaline variant was already mentioned earlier in the thread. Read again!

 

[Riemann Zeta]

I would be willing to try the constrained analogue TCB-2, but all of these N-methoxy-benzyl compounds sound like they are simply way too potent to ever be considered suitable for human experimentation.

Another ultra-potent psychedelic that has always interested me is dimethylazetidinyl-lysergamide. For some reason, I am not allowed to post attachments (that capability died when the board went down for a while a few weeks ago), or I'd post a structure. The reference is Nichols et al (2002) in J Med Chem. I have spoken to one person who has tried a small dose of [(2S,4S)-dimethylazetindinyl]-lysergamide who claimed that it was like LSD without "the bells and whistles," that is, it was a more mental and less visual ergoloid.

With all that ring strain on a cyclobutyl amide, one might worry about ring-opening and subsequent in vivo alkylation potential. If this does indeed occur, it might indicate that the azetidinyl- compounds could be carcinogenic; but since the required dose is smaller than that of LSD, the overall carcinogen exposure would be considerably less than, say, a puff of cigarette smoke.

 

[dread]

You can upload the images in your gallery and then copy the link on your post. That's how I did it.

 

[Erny]

What about the Br-DragonFly-NBOMe-hybrid?

It has a monstrous affinity according to Heim, and potency probably not that prominent, with it's logP = 4.

dread, I see a mistake in your drawing.

And all that chemical masturbation is boring. All the modifications above are obvious. And do not offer anything attractive.

 

[dread]

Oops.. true. Well, you can imagine the carbon between the amine and the phenyl... that's what happens when you do things sloppily.

fixed.


Here's a stupid idea... but it looks kinda cool!

 

[Schlaang]

At a festival i saw one guy who snorted 4 mg of NBOMe-2C-I within 1 hour and didn't feel any effect at all.
With same stuff some other people shared 2 mg for 5 persons and all of them was tripping quite intense.

edited out event name - nuke

 

[EN21]

N-benzyl-tryptamines

Glennon once published a paper on benzyl-tryptamines as potent agonists. The 4-Bromobenzyl-5-MeO-T derivative being one of the most potent.

I only once read anywhere about oral inactivity to about 3 mg.

Anybody who heared about nasal administration of N-benzyl-tryptamines?

 

[vecktor]

Glennon once published a paper on benzyl-tryptamines as potent agonists. The 4-Bromobenzyl-5-MeO-T derivative being one of the most potent.

I only once read anywhere about oral inactivity to about 3 mg.

Anybody who heared about nasal administration of N-benzyl-tryptamines?

they turned out later (heim) to be antagonists at 5ht2a,

 

[EN21]

they turned out later (heim) to be antagonists at 5ht2a,

Thanks. But isn't that weired?
But I also don't understand why NN dialkylated Phens are inactive whereas NN dialkylated tryps are active.

 

[nuke]

Examine the structure overlay; you're substituting on the indolic nitrogen at the same place where you're substituting on the amine in PEA. Aside from that they bind differentially at 5HT2A.

 

[dr.psilo]

Sorry if I may ask the obvious: What are you referring to with the term "simple dimethoxy"?

So, if you would consider NBOMe-TCB-2 *) to be a 'CW candidate', I assume that you think it's active... What about the Br-DragonFly-NBOMe-hybrid? I would expect it to be somewhat of a veeeeery slow onset but with hellish potency.

- Murphy

*) I assume we speak about this one:

"2CBCB-NBOMe" (above structure, racemate)
Ki @ r5HT2A = 0.220 +/- 0.004
Ki @ h5HT2A = 0.27 +/- 0.01
Ki @ r5HT2C = 0.46 +/- 0.03

See Braden MR. "Toward a biophysical understanding of hallucinogen action" PhD Thesis presented to Purdue University, May 2007 (should be available for free from theses search databases, though those databases are not free)

An N-benzyl of the "flys" has not been made (yet).

aloha
psilo

 

[MurphyClox]

Thanks a lot for the data! BIG UPS!

 

[dread]

How about switching that cyclobutene on the other side, as in another yet unsynthesized chemical 2C-G2? This would be NBOMe-2C-G2.

CBA to draw it right now, but it would have like 3,4-dimethylene substitution on the benzene ring...

 

[Erny]

erny, which 3,4,5 phenes were tested besides the mescaline derivitive? what is the bomscaline trip like?

Mescaline-NBOMe shares the mental clarity of mescaline, and lacks some of it's side effects, particularly nausea. I am not a mescaline fan, but in my opinion it has no real advantages over plain mescaline, considering possible routes of administration and the dose. It is really better for such things to be active orally. 3,5-dimethoxy-4-allyloxy-PEA-NBOMe is inactive up to some tens of mgs.

why does nichols have a methoxy group off the benzene instead of a c=o like in lsd? (well, thats where the c=o in lsd is im asuming)

A thing to interact with the methoxy group is not necessarily Asn 343. In fact, we do not know the exact residue, and there appear to be more than one candidate.

"2CBCB-NBOMe" (above structure, racemate)
Ki @ r5HT2A = 0.220 +/- 0.004
Ki @ h5HT2A = 0.27 +/- 0.01
Ki @ r5HT2C = 0.46 +/- 0.03

See Braden MR. "Toward a biophysical understanding of hallucinogen action" PhD Thesis presented to Purdue University, May 2007 (should be available for free from theses search databases, though those databases are not free)

What are those constants for? An ability to displace something, an agonist, radiolabeled DOI, I suppose? If so, they do not look very promising.

An N-benzyl of the "flys" has not been made (yet).

Oh yes, they have been made.

Those are tables from Ralf Heim dissertation. And higher potency doesn't always follow higher binding affinity, as I have already mentioned.

 

[dread]

So the hydroxybenzyl is actually more potent than the methoxybenzyl? Or did I read this way wrong?

 

[IGNVS]

erny thats some interesting stuff! but could you please explain what you mean by "A thing to interact with the methoxy group is not necessarily Asn 343. "

also, what about the methyl, ethyl and propyl groups at the 4 position? have they been made? i would assume if this inverse potency tendency applies the 2cd-nbo-me would be rediculous!

 

[dr.psilo]

What are those constants for? An ability to displace something, an agonist, radiolabeled DOI, I suppose? If so, they do not look very promising.

Sorry, Ki values are all vs. 125I-DOI and are in nM. It is not an improvement on the regular 25I-NB series, however it is still selective for 2A vs. 2C and is sub-nanomolar affinity.

Note also that "potency" does not necessarily have anything to do with hallucinogenic activity.

aloha
psilo

 

[Erny]

also, what about the methyl, ethyl and propyl groups at the 4 position? have they been made? i would assume if this inverse potency tendency applies the 2cd-nbo-me would be rediculous!

I have a constant feeling people do not read the whole thread before posting. So I'll quote myself once more.

The activity of bomamines in humans are sometimes inverted: NBOMe-2C-I requires 500-1000 mkg for a trip, NBOMe-2C-B - 500-800, NBOMe-2C-N - 400-700. The most active one I know about is NBOMe-2C-C with 200-500 mkg. Still, NBOMe-2C-D is less active than all theese, NBOMe-2,4,5-trimethoxy-PEA is many times less active, though I don't know the exact dose.

I'd suspect potency to increase in a row Me < Et < Pr, if the reverse order in I < Br < Cl serie is purely an issue of real affinity, and something like Me ~= Pr < Et if it is an issue of pharmakokinetics. Both issues may affect activity in human however, and I'd still be waiting for propyl to be one of the most active ones.

erny thats some interesting stuff! but could you please explain what you mean by "A thing to interact with the methoxy group is not necessarily Asn 343. "

I am talking about the docked pose of LSD as in "classical" Nichols 2002 model, where carbonyl oxygen of diethylamide group interacts with asparagine residue 343. They also suspected Asn 343 to form a hydrogen bond with oxygen in NBOMe 2-methoxy group. Both suggestions appeared to be wrong, as we know now from the paper dr.psilo pointed at:

If the hypothesis is valid that N6.55(343) interacts with the amide oxygen of ergolines and the polar ortho-substitution of the N-Benzyls, one would expect a marked decrease in binding affinity and/or functional activity at the h5-HT2A/N343A mutant receptor for these compounds. Surprisingly, this effect was not observed. As indicated in Figure 4.8, the affinity for LSD actually increased slightly, the other ergolines and half of the N-Benzyls were indistinguishable from wild type, and the remaining N-Benzyls had only slight decreases; the potencies for the ergolines and most of the N-Benzyls were decreased, but only slightly. As with affinity, the changes of intrinsic activity were either slight or indistinguishable from wild type, with the exception of LSD, where there was a - 25% shift, and 25I-NB, which actually increased slightly. Due to the 100-fold shift in functional potency of serotonin, the saturating dose of serotonin used for normalization purposes may not be fully stimulating. Although that was not generally observed in the raw counts for the assays of wild type and mutant receptor plates (data not shown), it may have artificially increased the calculated intrinsic activities of the other compounds at the h5-HT2A/N343A mutant receptor.

This is a really great piece of data, btw, big thanks!

Here is my own docking of LSD that looks very close to the "classical" Nichols one to bring more clarity in subject. The distance between that carbonyl oxygen and Asn 343 is little too long, 4,11 angstroms: