I Like to Draw Pictures of Random Molecules

[Nagelfar]

Reminds me of my "restricted rotational analog" of methylnaphthidate:

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InstaTardiveDyskinesamine?:

^Well might the acetyloxy get it to cross the BBB, and where on dopamine does it bind? covalent binding dopamine, would it at least have stimulant properties before (or at least wreaking less havoc than) going the way of oxidopamine?

Fentanyl + Diphenyl-2-pyridylmethane / (Desoxypipradrol)

 

[aced126]

A few words on the topic of dimerisation:

First, I think Sollipsis meant to post the following image (he posted the pyrazine derivative instead of the dihydropyrazine one).

As another example, here is the following dimerisation of cathinone:

Imine formation is reversible and also requires acid or base catalyst to reach equilibrium fast. If it is stored in neutrality, or in an excess of water, I don't think dimerization would be a problem. The problem is when the compound reaches the stomach, and its acidic conditions. As Sollipsis said, this can be circumvented by dosing on an empty stomach. Even better, administering it via rectal, nasal or intravenous routes would do the job. Once in the blood (neutral pH of around 7.4), dimerisation will reach equilibrium very slowly.

Even with this, I still don't think dimerisation should pose that much of a problem; in the stomach there is still quite a large excess of water in comparison to the concentration of the drug so even if equilibrium is fully reached, the concentration of the dimerized compound should be low. Also it wouldn't be entropically favourable.

Furthermore, if this was a problem then even secondary beta ketone amines (like methcathinone, methylone, mephedrone, bupropion even) would face this problem, only to form the enamine derivative instead. To illustrate:
Methcathinone dimerisation:

Meph dimerisation:

M1 dimerisation:

On a final note, take a look at this link: http://www.rxlist.com/wellbutrin-xl-drug/clinical-pharmacology.htm
"Absorption

Following single oral administration of WELLBUTRIN XL tablets to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion."
This would be dimerised Wellbutrin in the stomach supposedly:

Having said this, there is evidence to suggest dimerisation (of secondary amines at least, and likely primary amines) does not take place to a significant extent in the acidic environment of the stomach, probably because water is in excess. But then again, in bupropion there might be slightly more steric hindrance preventing enamine dimerisation.


I guess the only way of really testing all these hypotheses is leaving a beta keto phenethylamine in acidic aqueous solution for a while and measuring the equilibrium concentration of the original and dimerised compounds. If a significant amount of dimerised compound concentration is observed, then measure the rate at which it is formed in acidic conditions. If the rate is fast, then I guess another route of administration avoiding the stomach must be sought.

Sadly for me it'll be at least 5 years before I'll ever even have a possibility using a LCMS and NMR...

EDIT: Having thought about this, I'm now tending to think that primary bk-amines could actually dimerize (reversible) but then oxidize to aromatic pyrazines (irreversible) as DotChem mentioned. This would be less likely with secondary bk-amines because the 2 nitrogens would both have to form salts.

 

[roi]

 

[aced126]

Now one question: I thought talking chemistry is a NO NO on this forum. Let me know.

As long as it's not explicit synthesis I think it's fine.

 

[roi]

Not mine, from https://youtu.be/cmKo0_N7TJQ?t=1825. Looks like a piracetam analogue?

 

[sekio]

looks like a peptide... e.g. you are going to see oral PK problems

aced, those dimer molecules look like they would trivially lose H2 and aromatize given any sort of e.g. metal catalyst... more accurately the imine won't form if there is any water present because it's an equilibrium process.

 

[Friman1987]

 

[clubcard]

The alkenes are interesting. Anyone considered taking bk_2CB and replacing the -Br with a CH≡C- ?

 

[Solipsis]

Alkynes? Hmm idk has DOCN ever been considered?

 

[pharmakos]

DOCN sounds like "dosin'" if you try to say it out loud =p

 

[aced126]

I wouldn't be happy taking 2C-VI. Look at the methoxy group ortho to the vinyl moiety. That's gonna conjugate and increase the alkene's nucleophilicity loads. Could maybe alkylate cysteine and to a much lesser extent serine residues.

 

[DotChem]

was it a thread I missed on this:

 

[Solipsis]

I wouldn't be happy taking 2C-VI. Look at the methoxy group ortho to the vinyl moiety. That's gonna conjugate and increase the alkene's nucleophilicity loads. Could maybe alkylate cysteine and to a much lesser extent serine residues.

Styrenes have mutagenic epoxide metabolism anyway... but your suggested conjugation I am not following... you just mean the methoxy (methoxies) are ring activating? Or if you mean " O-methyl hexadienone "⁺ type conjugation products, isn't the para the most stable of all?

Also:

bridgheadket

^ Could you go all LSZ-style on the K structure? Apparently arylcyclopentylamines aren't even active while N-substitutions are pretty flexible. So if that position which overlays the alpha-carboxyl group of NMDA is so strict, why not constrict arylcyclohexylamines? Although technically I think that bicyclooctanes aren't even that constricting, still checking it vs. the norbornane might prove interesting... and it would certainly circumvent present laws right?
I suppose one could calculate the bond angles and tell you upfront that this is very similar to an arylcyclopentylamine and therefore a worthless endeavor..

^^ About the pyridinyl stims... I do wonder about pyridinyl dissociatives... but as far as phenylic bioisosteres go tiletamine seems pretty crude as a dissociative.

And finally: what about a lactone with the ring-opened version being rather lifelike cf. the NMDA carboxyl?

 

[Friman1987]

Styrenes have mutagenic epoxide metabolism anyway... but your suggested conjugation I am not following... you just mean the methoxy (methoxies) are ring activating? Or if you mean " O-methyl hexadienone "+ type conjugation products, isn't the para the most stable of all?

Epoxide metabolism of Styrenes can pass the cell membrane and reach the cell nucleus. Can the same thing happen with 2C-VI? The epoxide metabolism should make 2C-VI more polar.

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[sekio]

2c-vi will probabkly polymerize in the flask

 

[Dresden]

I think I really finally fried my brain on methamphetamine tonight. The hyperthermia!

 

[aced126]

I mean this kinda conjugation; idk it probably won't happen after thinking about it more but then again caution first. About the polarity of the epoxide compound itself: yeah it is more polar than simply styrene but it would still enter the cell in lesser quantities regardless. Can't seem to find any quantitative data on styrene toxicity.

 

[Solipsis]

Oh yeah so indeed the O-methyl hexadienone cation intermediate. It would probably react well with all kinds of residues in your tissue wouldn't it.. And like sekio said, that is, if you don't manage to polymerize it first by allowing radicals to initiate it.
You can't vitamin C that stuff straight ;p No thanks I'll pass on the psychedelic polystyrene foam forming in my tracts. Or I'd need to take a shitload of GBL to dissolve it all again.

 

[Friman1987]

Thanks for all answers. Like many mentions 2C-VI seems to have many things to be concerned about.

 

[Friman1987]

I tried to draw some N-substituted tryptamines that containing not more than 6 C atoms. Some of these molecules seem interesting, like PiPT or ETBT, MTBT. The 4 HO version of those can be interesting.

.....and Some random structure: