2C-CN and 2C-COOH

[Incunabula]

Hello, just reading this part in Pikahl, (under 2C-C), I got interested in knowing more about these 2 compounds.

The treatment of the 2C-B phthalimide described above, with cuprous cyanide rather than cuprous chloride, gave rise to the cyano analog which, on hydrolysis with hydrazine, yielded 2,5-dimethoxy-4-cyanophenethylamine (2C-CN). Hydrolysis of this with hot, strong base gave the corresponding acid, 2,5-dimethoxy-4-carboxyphenethylamine, 2C-COOH. No evaluation of either of these compounds has been made in the human animal, as far as I know.

Does any one have any information to share? all speculations wellcome
I´m just curious, could they possibly be worthwhile or...?

 

[chaos_destroy]

2c-cn probably is somewhat similar to 2c-b because the CN group is considered to be a pseudohalogen. The 2c-cooh would be too polar/charged because 4 position needs to be nonpolar.

 

[Astavats]

2C-pKet, 1-[4-(2-aminoethyl)-2,5-dimethoxyphenyl]ethanone, a similar compound to 2C-COOH was briefly discussed in "Towards a biophysical understanding of hallucinogen action". Compared to other know psychedelics (DOI, LSD, etc.) it preformed quite poorly in the binding studies at 5-HT2A. I recall reading an article that mentioned 2C-CN but I don't remember from who.I think it was Ralf Heim or if not perhaps R.A. Glennon.

Personally I'd guess neither would do well in regards to being a psychedelic.

Edit: I found the article I was thinking about, it's from Trachsel. It speculates on DOCN (and 2C-CN momentarily); "For the binding affinity at the 5-HT2A receptor, the comparison of the physicochemical data for 4-substituents (Table) suggests that compound 1 should have substantially higher affinity than 4-cyano-2,5-dimethoxyamphetamine (2d; DOCN) or the -demethyl congener thereof."

Synthesis of Novel (Phenylalkyl)amines for the Investigation of StructureActivity Relationships Part 3: 4-Ethynyl-2,5-dimethoxyphenethylamine (4-Ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN)

Compound 1 is 2C-YN. My memory was wrong, maybe 2C-CN is active.

 

[skillet]

Glennon published Ki's for DOCN and DOAc (the ethanone) - 46 and 81nM, respectively, at h5-HT2A labelled with DOI. TMA-2 had a Ki of 58nM.

The most interesting thing about this is probably that DOCN is the most selective for 2A among the 5-HT2 receptors known so far, 22-fold selective over 2C and 17-fold over 2B.

 

[Cortexiphan]

2C-COOH will probably be zwitterionic so even if it had high affinity it probably wouldn't cross the blood-brain barrier.

I believe Glennon made a number of DOI analogues with polar 4-substituents which retained high affinity for 5-HT2A but not cross the BBB. I think the compounds were investigated for the treatment of glaucoma.

 

[Incunabula]

Glennon published Ki's for DOCN and DOAc (the ethanone) - 46 and 81nM, respectively, at h5-HT2A labelled with DOI. TMA-2 had a Ki of 58nM.

The most interesting thing about this is probably that DOCN is the most selective for 2A among the 5-HT2 receptors known so far, 22-fold selective over 2C and 17-fold over 2B.

I´m not sure I understand that right.......But would that suggest that 2CCN and DOCN actually might be very psychedelic, especially it´s ratio between psychedelia versus side-effects?

A lower Ki means a larger affinity for the receptor, right? or how was that again

Thanks for the answers, folks. I love reading about this stuff, even though I´m clearly in over my head.

 

[skillet]

Yeah lower Ki = higher affinity. And yeah, they might be (probably are) active, but how/if selectivity might translate to lack of side effects or differences in the experience is really unknown so far. I don't think anyone has ever taken such a selective psychedelic, though 2C/DOCN will probably turn out to have affinity for a few other receptors too...

 

[Incunabula]

Okay, yeah, I see. I just thought that it was 5ht2c receptor, for instance, that was responsible for the nausea caused by many hallucinogens....?
More affinity for 2a and less for 2c, would be a good thing, or maybe it´s a lot more complicated than that. Guess it is.

 

[skillet]

I guess the question is, does 2A agonism alone account for the main effects of psychedelics? (I think it probably does, though obviously activity at other receptors is going to colour the experience somewhat.) It's been shown pretty conclusively that 2A agonism is essential for a psychedelic to be effective (ketanserin blocks most of the effects of psilocybin in humans, 2A knockout mice don't show the characteristic behavioural response to psychedelics...) but not that everything else is just icing on the cake.

It could be interesting to take a bunch of selective antagonists and work through them, in combination with a psychedelic, to see how blocking specific receptors alters the experience.

 

[sekio]

There's 2 pretty damning pieces of evidence that correlate psychedelic activity with 5-HT2A activity.
The first is: graphing 5-HT2a affinity versus psychedelic dosage in man is a fairly straight line.
The second: Selective drugs such as 25I-NBOMe are psychedelic, and 5-HT2a blockers work to terminate trips.

 

[skillet]

I'm sure you're probably right, but I'm not so convinced by your arguments. Graphing 2A affinity against 2B and 2C affinity will also give a fairly straight line. 25I-NBOMe and others are maybe slightly more selective than the 2C's, but not by much at all. And, like I said, just because agonism of 2A receptors is essential, doesn't mean that co-activation of another receptor isn't required. I admit it's a bit of a long shot, but it can't be ruled out.

 

[lysergication]

And those 25x-NBOMe doesn't seem prone to induce ++++ experiences, do they ? I've never had the opportunity to try these but from what I read they seem to lack a bit of deepness. Maybe this is because of their high selectivity ?

 

[skillet]

It's a bit early to tell, I think. Most of the 2C's don't seem very good at producing +4's either, though some sound more effective than others. And again, the 25X's don't seem to be much more selective than the 2C's, the idea that they are, I guess, comes from Heims thesis, and Nichols paper on tritiated 25I-NBOMe.

Heim references Glennon for that assertion, who wrote that 25B-NB is 300-fold selective for 5-HT2A over 2C, but he's comparing the affinity at agonist labelled 2A receptors with that at antagonist labelled 2C receptors. If you look at the data with ketanserin labelled 2A receptors, the selectivity drops to 5-6x.

Nichols measured the affinity of 25I-NBOMe at something like 0.04nM at 5-HT2A, and got affinities at 2B and 2C from the PDSP of 231 and 2nM, respectively. This would be a selectivity of 50x for 2A over 2C, but, again, that's comparing agonist labelled 2A receptors with antagonist labelled 2C receptors.

Ettrup published affinities from the PDSP for several 25X-NBX compouds, and got selectivities ranging from around 2 or 3 to 37x for 2A over 2C, and around 0.7 to 7 for 2A over 2B*. Selectivities at other receptors seem a bit random, overall I don't think you can say they're more selective than 2C's, just a bit different.

*2B was measured against an agonist, 2A and 2C against antagonists. So selectivity for 2A over 2B is likely higher, Glennon found from 4-60x for several DOX's when both receptors were labelled with agonist radioligands.

 

[immad]

5-MeO-DMT is highly psychedelic and an affinity that's 1000 times higher for 5-HT1a than for 5-HT2a according to psychedelics and the human receptorome. Personally, I suspect 5-HT1a to be connected with the "mysticality (?)" of psychedelics.

The 2C's I've tried so far (2C-E, 2C-P, 2C-C and threshold 2C-T-7) and DOM don't seem that "mystical", while most tryptamines and especially 5-MeO-DMT seem to hit that sweet spot. So I guess there's more than 2A activation involved.

 

[sekio]

5-HT1a is definitely involved in e.g. 5-Meo-DIPT and MDMA's activity.

 

[Cortexiphan]

I believe that agonism at 5-HT1A must play some sort of potentiating role in tryptamine and ergoline psychedelics. This would also explain why LSD is so potent despite a modest Ki and low intrinsic activity at 5-HT2A receptors. It would be interesting to see a study that compares the effects of tryptamines/ergolines with and ithout blocking of the 5-HT1A receptor.
Has anybody heard of such a study?

 

[skillet]

Yeah the 1A affinity of tryptamines is interesting. I was thinking about 1A agonists that could be taken together with a 2C, to see what happens But the only one I can find that's quite common is buspirone, I'm not sure it would be a strong enough agonist though, and the selectivity doesn't sound great.

A tryptamine with a 1A antagonist would be a good alternative, I'm not aware of any studies on it. And, again, I don't think there are any commonly available selective antagonists to play with at home.