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

[skillet]

Is there any data/anecdotal evidence that the unsubstituted N-benzyl PEAs have lower efficacy than the parent compounds? How have other N-benzyl PEAs panned out?

 

[tryp2fun]

Careful guys:

the identity and purity of this compound is open to question. I would begin with lower doses than these (in the range of NBOMe substituted 2Cs) until more reports flow in.
...
It would be really interesting if this were to pan out though, as it would begin to map the SAR of this class of compounds. It would seem at first pass that a ring substitution on the 2-benzyl is key for heightened conformation at the 5ht2a receptor.

ebola

The compound was obtained from a reliable source and has an NMR confirming the structure. The titration started at 250 ug, then 500 ug, 1 mg, 2 mg, and 4 mg sublingually, when a threshold was observed, at 2 week intervals. Subsequent trials were at 6, 8, 10, 12 and 14 mg.

 

[nuke]

Is there any data/anecdotal evidence that the unsubstituted N-benzyl PEAs have lower efficacy than the parent compounds? How have other N-benzyl PEAs panned out?

Pretty sure the affinities were lower in the Heim dissertation

 

[ebola?]

The compound was obtained from a reliable source and has an NMR confirming the structure. The titration started at 250 ug, then 500 ug, 1 mg, 2 mg, and 4 mg sublingually, when a threshold was observed, at 2 week intervals. Subsequent trials were at 6, 8, 10, 12 and 14 mg.

 

[skillet]

^ lol. Yeah the affinities are lower than the 2-substituted benzyls, but still higher than the parent compounds. Amanitidine said about efficacy, which I'm not so sure about...

 

[amanitadine]

^^^ Nor am I, as affinity is what I was intending to say. ;D I can't quite remember but didn't Shulgin make a few N-Benzyl PEAS long ago that were inactive? I distinctly remember at least N-Benzyl MDA being in PIHKAL because the comments were interesting...(unrelated to N-Benzyl MDA iirc)

 

[skillet]

Hehe ok. I don't know about Shulgin but Glennon made 25B-NB (PMID: 8027974) and it had about 2x the affinity of 2C-B. He also did some 4-substituted benzyls, 4-Br being the best with about 10x the affinity of 25B-NB; there's no efficacy data in that paper though.

 

[Hyperthesis]

Plain 2C-B showed a pEC50 of 7.20, with an Emax of 58%.
25B-NBOMe had values of 9.66 and 38%, respectively.
25B-NBOH had values of 9.58 and 35%, respectively.
25B-NBOCF3 is practically inactive, with an Emax of just 6%, and ca. 100fold less affinity to r5HT2A.
25B-NB was not presented in Ralf Heim's thesis; the only (!) publication dealing with this derivative is by Glennon et al. in Journal of Medicinal Chemistry (1994), 37(13): 1929, which presents only affinity but no efficacy data, as was already pointed out by skillet. Extrapolating from what is available, I'd estimate that 25B-NB is probably several orders of magnitude less potent than 25B-NBOX and, therefore, do the results of tryp2fun's bioassays cause a raised eyebrow on my side (see the last paragraph of this post).

Short underline to the above data:

"pEC50" = partial agonistic efficacy
"Emax" = intrinsic activity; both refer to measured by functional in vitro assay using cylindric segments from rat tail arteries (ie. r5-HT2A-receptor data)
"relative potency" refers to 5HT, which is set as 1.​

More details how these values are calculated can be found in Jenkinson et al., Pharmacol Rev (1995), 47: 255.

For non-german speakers, who can't read resp. understand Heims's diss, I refer to J Comput Aided Mol Des (2011), 25: 51, which presents an up-to-date SAR-discussion of the results of Elz' group.

Everything I have seen seems to point that the bulky oxygen is needed there for the increased efficacy, whether it be a MeO, MDO, or HO group.

Sidenote: What is MDO referring to? CD3O or methylenedioxy?


@tryp2fun: I do not ask for any sources, but please let me point out that the reliability of RC-products is quite doubtful nowadays. Hence, whereever your sample came from, I hope you have some really good reasons to believe that your sample contains indeed what the label states. Would it go to far to ask for for a scan of the NMR-spectrum?

 

[amanitadine]

^^^ Thank you for that! And yes, by MDO I was referring to the methylenedioxy bridge. Bad nomenclature, me apologies. Intending to do some assays of a few of the NBMD subsituted 2C's soon (ish).

 

[skillet]

^^ Why the raised eyebrow? I agree the material is quite possibly not what it's claimed to be, but oral inactivity, the duration, and the slightly increased potency over 2C-B suggest it could well be the right stuff.

^ The NBMD's do sound interesting, mostly because of the increased selectivity over 5-HT2C of 25I-NBMD...

 

[Hyperthesis]

^^ Why the raised eyebrow?

This:

I agree the material is quite possibly not what it's claimed to be, but oral inactivity, the duration, and the slightly increased potency over 2C-B suggest it could well be the right stuff.

First, the extrapolation from the available data suggests otherwise. Second, the current habits of the RC-market strongly suggest that the material is more probably a fake than it is genuine. Maybe it's one of the other available N-benzyl-PEAs, but cut, to lower the potency. Maybe something entirely different...

I was asking carefully, because I have no clue where tryp2fun got his sample from and didn't mean to sound offending. It could be a fake, without him knowing this. Was the NMR provided by the source? How can we be sure that it is actually a genuine spectrum, but from an entirely unrelated sample? It could also be absolutely what tryp2fun stated.

______________________________________________________
Related, but off-topic (sorry 'bout that)

It is somehow funny to see, how vendors resp. producers adapted to the demands of their more educated customers.
When the first doubts about the declared purity of a product were expressed, producers delivered fantastic numbers; of course was their product always >99.5% pure. After some time it turned out that some of these values where purely fictional, which made customers ask for copies of the chromatograms. Et voilá, they were delivered. But who tells you that your chromatogram is actually from exactly the same sample, which you received, and not just from a tiny fraction, especially purified only to provide proper data (a behaviour to be suspected with all analytical methods, btw)?
Being concerned about the purity, customers asked for GC-MS or HPLC data. Sometimes, these were delivered, but the quality was in many case ... errr ... doubtful, which suggested that the producer either didn't know how to prepare a proper chromatogram (not an indication for professional standards), or the amateurish attempt to conceal otherwise compromising details (an indicator that you just spent some money on bullshit).
Then - hear ye! - customers asked for NMR. These were already more difficult to fake, but nonetheless was it tried several times:

* I have seen NMR-spectra posted here at Bluelight and in related places with a resolution so low, that you couldn't even read the printed numbers.
* I've seen spectra without integrals, chemical shifts and other appropriate data (= worth less than toilet paper).
* I've seen spectra of the wrong compounds, sometimes not even remotely related by structure.
* I've seen spectra (HPLC in this case), which were entirely labeled in chinese, intended for english-speaking customers.
* I've seen calculated spectra.​

And again, in the cases where the spectra looked as they were supposed to, the question was raised how a customer can be sure that the data in his hands actually belongs to exactly the sample in his hands?

Irony of fate, by requesting NMRs, it is now next to impossible to verify the provided data for >99% of all drug users. Anyone here with access to a NMR-spectrometer, and preferably GC-MS, too, please raise your hand.

After all, I would think that requesting something as simple as a melting point, which actually can't be predicted with sufficient accuracy, could to some extend be the answer. In former days, when a chemist had prepared a previously not known compound, the melting point was thought to be a specific hallmark. When another chemist repeated the work and found a different melting point, preferably higher (=purer!) as the former one, then this was now the correct hallmark, and so on. As soon as only one single, pure sample of a drug gets in the hands of somebody with a melting point apparatus, it gets incredibly hard to cheat your customer. This person could actually be a rogue chemist and not somebody ordering from China.
A melting point could help to check (to some degree) with comparably little costs the purity and identity of a drug, well, provided that a compound has a sharp melting points. But this prerequisite is fulfilled by the vast majority of salts, ie. (almost) all XYZ-NBOMe-derivatives, all cathinones, all PCP- and ketamine-derivatives. Dunno about the AAIs though. I think these groups make up the largest part of the currently offered psychoactives.

But alas! I forgot that nowadays "research chemicals" are sold as smoking blends or (laced with many other crap) prefilled into capsules, or dark brown 'n sticky powders (99.8% pure! Buy today and get one for free!). Melting point, pah! Silly me...

 

[skillet]

Good points, I'd apparently forgotten that the people who sell RC's are often total scum (edit: or just clueless maybe). And yeah, I'd never trust a vendor supplied spectrum. I guess it would be possible to cut the stuff, but that would be highly risky for a vendor to do, unless they can make it completely (or at least very close to) homogenous. It seems unlikely they could do that, maybe they just don't give a crap.

How do you think extrapolation of the available data suggest it's not what it's thought to be, though? It sounds reasonable to me.

And I agree that melting point, possibly after a recrystallisation, could be a good way for amateur experimenters to verify the identity of their material. It should be pretty easy to make the apparatus, and it only takes one person with a particular batch...

 

[tryp2fun]

Plain 2C-B showed a pEC50 of 7.20, with an Emax of 58%.
25B-NBOMe had values of 9.66 and 38%, respectively.
25B-NBOH had values of 9.58 and 35%, respectively.
25B-NBOCF3 is practically inactive, with an Emax of just 6%, and ca. 100fold less affinity to r5HT2A.
25B-NB was not presented in Ralf Heim's thesis; the only (!) publication dealing with this derivative is by Glennon et al. in Journal of Medicinal Chemistry (1994), 37(13): 1929, which presents only affinity but no efficacy data, as was already pointed out by skillet. Extrapolating from what is available, I'd estimate that 25B-NB is probably several orders of magnitude less potent than 25B-NBOX and, therefore, do the results of tryp2fun's bioassays cause a raised eyebrow on my side (see the last paragraph of this post).

Short underline to the above data:

"pEC50" = partial agonistic efficacy
"Emax" = intrinsic activity; both refer to measured by functional in vitro assay using cylindric segments from rat tail arteries (ie. r5-HT2A-receptor data)
"relative potency" refers to 5HT, which is set as 1.​

More details how these values are calculated can be found in Jenkinson et al., Pharmacol Rev (1995), 47: 255.

For non-german speakers, who can't read resp. understand Heims's diss, I refer to J Comput Aided Mol Des (2011), 25: 51, which presents an up-to-date SAR-discussion of the results of Elz' group.



Sidenote: What is MDO referring to? CD3O or methylenedioxy?


@tryp2fun: I do not ask for any sources, but please let me point out that the reliability of RC-products is quite doubtful nowadays. Hence, whereever your sample came from, I hope you have some really good reasons to believe that your sample contains indeed what the label states. Would it go to far to ask for for a scan of the NMR-spectrum?

​

In this paper by Nichols, (Mol Pharmacol. 2006 Dec;70(6):1956-64. Epub 2006 Sep 25. Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Braden MR, Parrish JC, Naylor JC, Nichols DE.) he compared 2CI, 2CI-NB, and 2CI-NBOM, among others, and found that the affinity of 2CI-NB is about twice that of 2CI, and the efficacy of 2CI-NB is actually higher than 2CI.

 

[(zonk)]

ugh, i'm getting sick of people quoting old Shulgin entries. I'm not knocking the guy but people don't really know how to understand what info he's establishing. 1st off, read the ENTIRE entry(it's not so much what he says-but what he DOESNT say). MANY of the compounds in PIHKAL weren't even tested by him or his immediate friends, alot of the entries are very vague 2nd hand info. And remember that most of his compounds were tested orally and many at subthreshhold levels so that an active dose had not been reached. These are mostly NOT extensivly tested in his book. Most compounds should be refered to as "undetermined" not "inactive"

Case in point... 3,4-DMPEA (i like to call "DMP" like DMT)was said to b inactive, yet I do not consider myself very smart at all but I immediatly assumed it was active but required MAO-B inhibition. Further reading/research came across many published findings that(atleast in rats)it was comparable to mescaline. And indeed(w/maoi) it IS

 

[skillet]

^^ The NMR looks right (integrals would be, uh, nice, and a higher concentration, D2O isn't the best solvent for these), but where did it come from? Oh yeah, I forgot the compound was in that paper. The potency is higher but intrinsic activity is slightly lower than 2CI.

That's interesting zonk, yeah I get the impression several more of the compounds would be active at a higher dose or with MAO inhibition, TMA-3 for example. And wasn't there an article linked here fairly recently about someone who took one of the alpha-ethyl PEAs at a really high dose (200mg or something) and found it to be psychedelic (though I can't remember much about the description of the effects)?

 

[Hyperthesis]

In this paper by Nichols, (Mol Pharmacol. 2006 Dec;70(6):1956-64. Epub 2006 Sep 25. Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Braden MR, Parrish JC, Naylor JC, Nichols DE.) he compared 2CI, 2CI-NB, and 2CI-NBOM, among others, and found that the affinity of 2CI-NB is about twice that of 2CI, and the efficacy of 2CI-NB is actually higher than 2CI.

Ahhh, yes, Sir. That looks indeed persuading. How could I miss that one