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I Like to Draw Pictures of Random Molecules

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belligerent drunk said:
You're right about the nitrogen in the indole. It usually is protected though, just as a precaution.
Click to expand...

As you said the only way it can be protected is by addition of a strong base first for deprotonation. Why add 2 steps when you know that the trifluoromethylation conditions doesn't require base? The only way a trifluoromethyl group will get on the indolic nitrogen is if while trifluoromethylating you add base. I just read Solipsis' link, and it seems like you don't need a strong base.

https://en.wikipedia.org/wiki/Trifluoromethylation#Electrophilic_trifluoromethylation

In one of the pictures it shows a TFM group adding onto the sulphur and not onto the nitrogen, with 97% yield. If it's selective for that then I don't think TFM will be adding onto the indolic nitrogen in DMT.
 
If you put two TFM groups on the nitrogen's amine, then you decrease its basicity by withdrawing electron density and thus likely lower affinity.
 
Also, won't it be so polar that it has a harder time entering the brain? Vaped DMT is a fantastic flash, but to be honest I think the kinetics are way too fast. Things like 4-AcO-DMT have a much more reasonable pace, helps with having a more meaningful experience.. Then again slow acting less potent versions of DMT may not be overwhelming enough for MAO?

I have no idea if the trifluoros prevent MAO breakdown..

[Maybe this synth talk is exceeding a bit if we would keep going? ^^]

Had this morph-AMT idea but it's apparently unpromising:

amtmorph.png
 
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Alpha-methylated tryptamines are indeed mostly unpromising. Maybe the beta position would be a better choice?

3-(2-morpholinyl)-indole

3-%282-morpholinyl%29-indole.png


It actually already exists and even has a CAS number. But absolutely no papers explaining what it does. Interesting!
 
adder said:
If you put two TFM groups on the nitrogen's amine, then you decrease its basicity by withdrawing electron density and thus likely lower affinity.
Click to expand...

True that, assuming the charged nitrogen interacts with a negative residue, which is very likely. With that logic, will electron donating substituents increase potency? N-monomethyltryptamine would have a much more basic nitrogen yet it seems to have similar potency to DMT. How can those results be explained? Maybe having a hydrogen donor reduces potency by creating unfavourable interactions. Maybe it is metabolised quicker.
 
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That's what I'm hoping for! Orally active and equipotent to DMT. It would be simply amazing.

In case two TFM groups end up reducing potency, we can also have the N-Trifluoromethyl version alongside. So we have NTFMT, MTFMT and DTFMT.

If it doesn't work very well, we'll always have the 4-AcO-DMT counterpart too!


4-acetoxy-N-methyl-N-trifluoromethyl-tryptamine.png
 
Solipsis said:
Also, won't it be so polar that it has a harder time entering the brain?

I have no idea if the trifluoros prevent MAO breakdown..
Click to expand...

I don't know whether it would be more or less polar. The thing is, when you add a fluorine substituent onto benzene, it gets slightly more lipophilic, but when you add it onto an aliphatic carbon chain, it gets slightly more hydrophilic. I guess one would just have to make this and experimentally determine logP. If the fluorine was a chlorine or bromine instead, then that would very likely make the molecule much more lipophilic, as chlorine or bromine substituted onto benzene or aliphatics increases lipophilicity much more than fluorine.

Used this website to predict logP for indole, dmt and d(TFM)t. Predicted 2.16 for indole, and experimental value is 2.14 suggesting the prediction for these compounds would be relatively accurate.

For dmt it predicted 2.30
d(TFM)t was 4.12 surprisingly. Very high. As expected, it predicted 5.97 and 6.76 respectively for the chloro and bromo derivatives. Can anyone more advanced in chemistry explain why logP was increased by so much. I'm not too sure really on why fluorine increases logP slightly on benzene but decreases it slightly on an aliphatic. I'd be grateful for a nice explanation.

As for metabolism, all I could speculate was that it would increase half life.

http://www.nature.com/nrm/journal/v13/n5/fig_tab/nrm3327_F1.html

So obviously taking a big assumption here that demethylation by MAO works in a similar way to the enzymes described above in histone demethylation. Someone studying/with a degree in biochemistry here please correct me if wrong.
In reaction a), it seems that the molecule of oxygen gets one hydrogen from the methyl group to be removed and one from the charged nitrogen. Well if the methyl group had 3 fluorines on it, then the oxygen would have to attack the fluorine. As far as I know that would make for an unstable compound. The wiki page on dioxygen difluoride says it reacts nearly every chemical it encounters. So that would suggest dioxygen monofluoride monohydrogen is of similar reactivity and would not be likely to form as much as hydrogen peroxide when metabolising normal DMT.

For reaction b), I would suspect the addition of a hydroxyl onto the TFM would be hard, and furthermore when that moiety leaves to form difluoroformaldehyde, well... I can't even find any information on that chemical. So yeah my gut instinct is it would really increase half life.


Just thinking about it now, this compound would have a high logP and increased resistance to MAO. So maybe it could be oral and equipotent to DMT (less affinity but hopefully increased logP makes up for it).
 
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Solipsis said:
Also, won't it be so polar that it has a harder time entering the brain? Vaped DMT is a fantastic flash, but to be honest I think the kinetics are way too fast. Things like 4-AcO-DMT have a much more reasonable pace, helps with having a more meaningful experience.. Then again slow acting less potent versions of DMT may not be overwhelming enough for MAO?

I have no idea if the trifluoros prevent MAO breakdown..

[Maybe this synth talk is exceeding a bit if we would keep going? ^^]

Had this morph-AMT idea but it's apparently unpromising:

amtmorph.png
Click to expand...

What molecule do you have in mind with the polarity? Two trifluoromethyl groups won't make it more polar.

To aced, I'm not really sure why the logP increases so much for the TFM derivative. It could be because DMT can be a much more significant hydrogen bond acceptor at the tertiary nitrogen than DTFMT, because the TFM groups are quite bulky plus they lower the basicity of said nitrogen. You have to remember though that at physiological pH the nitrogen is protonated so the latter has no effect, I'm not sure if the program takes that into account. TFM groups are, I would say, on the non-polar side of things; yes, fluorine is very electronegative, but still the negative charge is quite diffuse in TFM even with fluorine atoms, so the relatively non-polar bulkiness could add to the lipophilicity? I'm not entirely sure of that, could be wrong - I don't really know how polar/non-polar TFM group is, just speculating.

I don't really have a good explanation for the difference between fluoroaryl and -alkyl logP behaviour. Maybe because the electron pair on fluorine resonates with the aromatic ring? Not an expert in chemistry, so maybe someone who knows what they're talking about could chime in.

As for the metabolism of the N substituents, C-F bond is hard to break, fluoroalkanes are very unreactive. Neither reaction would work. So yes, that would increase half-life.
 
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Dresden said:
It's hard to say without testing it, but the synthesis looks really really hard. It would have to be made from scratch if what I'm thinking is right. But I don't want to discuss synthesis of course.
Click to expand...

Yeah no kidding, but this is the random molecules thread not the commercially viable ones =D

0qNnMfi.png


peoRnum.png

(ignore the highlighting there)
 
roi said:
48 hour energy:

2-%5B(4-fluorophenyl)(phenyl)methyl%5Dpiperidine.png
Click to expand...

p-fluoronated desoxypipradrol?

I still think, if I had time to try out many different models in 3D, that making the cycloalkane with nitrogen in a more constrained "boat" formation would be best, since those seem to optimize binding with the cocaine analogues with which it is easiest to begin with as a starting compound for those as semi-synthetics, but what if we tried with the above, or say, MPH?

This is me shooting in the 2D dark, someone with time might want to align the below "boat" ring to a back-bridged phenyltropane, make sure the nitrogen winds up in roughly the same spot:

wpKFo.jpg


The way the ring is torsioned has a lot to do with it. But there's an attempt at making something more "form-fitted" like hand in glove, to MAT
 
Much more activated ring system than 5-Br-DMT (which is now on the market):

3-dimethylaminoethyl-4-methoxy-5-bromo-7-methoxyindole.png


Yes, this one's clever.

* * *

In other news,

6-acetoxy-6-desoxy-2,3-methylenedioxy-3-desoxymorphine.png


I can almost taste it!!! The thought of a psychedelic opiate (like pentazocine, I guess) turns me on. Note the MMDA pharmacophore.

This is MMDA, for those of you who don't know or remember:

1-(3,4-methylenedioxy-5-methoxyphenyl)-2-aminopropane.png


MMDA is very sedating and thusly is best combined with methamphetamine. However, in an opiate that's good. Also, note the 6-acetoxy (a la heroin) group, making this one an IV drug. If you don't want an IV drug, then I would suggest:

6-oxo-6-desoxy-2,3-methylenedioxy-3-desoxymorphine.png


This one should be good orally. :)
 
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What's the rationale behind the 6-acetoxy group? It's not really necessary for opioid activity and will most likely hinder psychedelic activity so I'd say it would better be left out. Same for 6-ketone.
 
Well, these structures are based on morphine, and morphine has a 6-OH but a 6-oxo or a 6-acetoxy can be derived from the hydroxy, and both make the entire molecule get into the brain much better than if morphine's 6-OH was just left there. Since these two molecules would likely be made from scratch, I guess you're right though. I was kind of always under the impression that they were necessary for activity or helped it somehow, but hey, my specialty is the amphetamines, not the opiates. Amphetamines are delightful and amenable to so many structural changes.
 
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Total noob question, I had O-chem well more than a decade ago and Pharmacology (not to any really advanced classes much less degree in either) not soon much thereafter, although I have tried to keep up on both informally, yeah, a lot escapes me, but whenever something does, I try to learn it so as to add to my fund of knowldge ... in ADD I always figure even if I grok 10% it's a good 10%, so I read ... but in terms of simple technical stuff could I just ask which chemical drawing software y'all are using to draw these molecules?

I have tried a few different ones both online in-browser for Linux and they don't make as pretty pictures and are a bit of a pain in the ass. You all seem to be using the same thing and it's probably Googleable but I'd like to know so I could present of my thoughts (like I was saying before about 4-MAR analogs) more visually....
 
Great question!

http://opsin.ch.cam.ac.uk

You have to be able to sort of be able to name what you are trying to draw, and you will need to read the instructions I gave about 10 pages back in this thread for using it. It just involves some copying and pasting, creating a website for your drawing, copying that url, and pasting it into here between a URL and a /URL (but with square brackets around them!) before posting it here on bluelight.

Other people prefer MarvinSketch. YMMV. Good luck! Opsin is great once you get the hang of it. If you get stuck and have questions, just ask.

Aw, shucks, let me just run down how to do it:

-go to above website
-erase 2,4,6-trinitrotoluene from the entry screen and type "2-methylamino-1-phenylpropane"
-press enter
-see your structure
-copy the name of the structure in the box above the drawing using your computer's Copy function
-in the address bar, type http://opsin.ch.cam.ac.uk/opsin/ Paste "2-methylamino-1-phenylpropane" which you just copied followed by .png immediately after the "e" in propane
-press enter, the computer will take you to a new url with just your molecule drawn on it
-copy the entire address bar of the url using the Copy function
-return to this thread in bluelight
-make a post with [ then URL then ] then Paste then [ then /URL then ] with no spaces anywhere
-press enter
-Viola, your molecule is online for the world to see!!!
 
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4-bromo-2-methoxy-5-trifluoromethoxyphenethylamine.png


What about this one? Both the 2-EtO and methylthio analogues are weaker than the regular 2Cs. A trifluoromethoxy group wouldn't be too big and might even produce interesting results.


But let's not get overboard with fluorine or we might contribute to ozone depletion :)


4-chloro-perfluoro-2%2C5-dimethoxy-phenethylamine.png
 
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