• N&PD Moderators: Skorpio | someguyontheinternet

I Like to Draw Pictures of Random Molecules

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Well chemicalize.org is still crapping out on me. Anyone else have this problem? Is it my location? (my library's connection?) I used that Osiris program, but it hangs whenever I input by SMILES or CAS reg. #., and after I get to a size of a drug roughly a few atoms bigger than cocaine it totally freezes on me (no pun intended: due to all the extra calculations of drug-likeness I am assuming)
 
1-(2,6-dimethylphenyl)-2-aminopropane.png


Lidocaine inspired amphetamine.

Put a para-hydroxy on there and you might have yourself a nice opioid. :P
 
Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?
 
Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?

Modeling it on Vyvanse (lisdexamfetamine), it should have probably twice to three times the duration of mephedrone? I suspect it would require a similar adjustment in dosage. Also since the enzymes responsible for the metabolism are in the red blood cells it would be longer acting regardless of RoA unlike, I think, "Captadrone." It'd be a bitch of a synth though.
 
Running with the Vyvanse theme, what if we replaced the amino acid with a biologically active tryptamine?

Somewhat fancifully ... Shroomphetamine.

(2S)-6-%5B%5B3-(2-Dimethylaminoethyl)-6-hydroxy-indol-4-yl%5D%5D-2-amino-N-%5B(2S)-1-phenylpropan-2-yl%5Dhexanamid.png
 
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Right, how would that molecule cleave; Also why are there a few out of place amino groups?

Off-topic: why does vyvanse even work? I mean, what advantages does it have over say N,N-dimethylamphetamine as a prodrug to (meth)amphetamine. Is it just that the lysine moiety is easily cleavable? Why does cleavage occur in the RBCs? Why can't it get cleaved in the stomach by peptidases? This guy seems to prove my point (not very scientific but we have grounds to believe this is true).http://www.bluelight.org/vb/threads...ersion-update-The-trypsin-method-is-confirmed
 
http://www.bluelight.org/vb/threads/405660-Paper-I-wrote-about-LisDex-to-D-Amp

There's this as well which is intriguing...lol

Furthermore, the half life of lisdexamphetamine itself is only 1 hour; that means that whatever amphetamine is going to be released is going to be released within that first couple of hours before the concentration of lisdexamphetamine becomes negligible. Having said that, I don't really understand how lisdexamphetamine is claimed to be a sustained release source of dextroamphetamine.
 
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Right, I actually just got a potentially good idea; any comments and expansions are appreciated:

N-(1-(benzo[1,3]dioxol-5-yl)-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide

N-(1-(benzo%5B1%2C3%5Ddioxol-5-yl)-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


Right, that was for fun, but the idea still holds; could a homeostatic equilibrium be maintained by administration of a selective monoamine releaser which releases the monoamine itself? I've definitely heard of anecdotal reports of people being able to abuse MDMA way longer than they should be able to and at much higher sustained frequencies by integrating 5-HTP into their use.

More derivatives:

N-(4-fluorophenyl-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png

N-(4-chlorophenyl-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


How about a really selective serotonin releasing agent? Could this be a potential antidepressant when coupled along with a built-in dose dependant 5-HT releasing mechanism?

N-(5,6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide
N-(5%2C6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


Off topic: does anyone know any brain enzymes which are specific to the brain and not really found anywhere else?

N-(indan-5-yl-propan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


And finally: this should be the most selective of all I'd say:

N-(1,3-dihydrocyclopenta[f] indan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide

N-(1%2C3-dihydrocyclopenta%5Bf%5D%20indan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png
 
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Right, how would that molecule cleave;

If I am wrong about this, that's why I called it "fanciful" :)

If I'm right, like so:

Sharman J and Pennick . Lisdexamfetamine prodrug activation by peptidase-mediated hydrolysis in the cytosol of red blood cells. Neuropsychiatr Dis Treat 2014; 10: 2275–2280.

Whether the psilocybin would remain intact, I'm not sure, that's where the "fanciful" part comes in again.

also why are there a few out of place amino groups?

I goofed. Fixed the original post above, I think.

Off-topic: why does vyvanse even work? I mean, what advantages does it have over say N,N-dimethylamphetamine as a prodrug to (meth)amphetamine. Is it just that the lysine moiety is easily cleavable? Why does cleavage occur in the RBCs? Why can't it get cleaved in the stomach by ? This guy seems to prove my point (not very scientific but we have grounds to believe this is true).http://www.bluelight.org/vb/threads...ersion-update-The-trypsin-method-is-confirmed

From Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010;6:317–327 (cited in ibid.)
LDX was not metabolized in vitro by SGF, SIF, or trypsin, supporting our view that any conversion of LDX to d-amphetamine in the GI tract in vivo is likely to be minimal.
 
How would this idea now compare if SSRIs were used instead? Desmethylsertraline is 50 times weaker than the N-methylated metabolite, yes, but it still has a Ki constant of 76nM and negligible constants at the other 2 transporters. So how about this:

Tryptaline

N-((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide

N-((1S%2C4S)-4-(3%2C4-dichlorophenyl)-1%2C2%2C3%2C4-tetrahydronaphthalen-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


Not sure whether this will be a substrate of the enzymes but the N-methylated version to hopefully yield sertraline itself:

N-methyl-N-((1S%2C4S)-4-(3%2C4-dichlorophenyl)-1%2C2%2C3%2C4-tetrahydronaphthalen-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


Tryptoxetine

N-methyl-N-(3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide

N-methyl-N-(3-phenyl-3-%5B4-(trifluoromethyl)phenoxy%5Dpropan-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


Norfluoxetine is still very selective in its own right, just a slight dosage increase might be needed.

N-(3-phenyl-3-%5B4-(trifluoromethyl)phenoxy%5Dpropan-1-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png


In fact this would probably be better as for everyone one molecule of norfluoxetine released, only one molecule of 5-HTP is released as well. And with the low SSRI dosage, little 5-HTP will be released anyway. So any increase in dosage helps. In fact (since all these drugs and 5-HTP have a MR of about 200), maybe 50-200mg of the molecule would be ideal each dosage as roughly this amount of 5-HTP would be released.
 
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aced126 said:
various interesting molecules

The 5-HTP one is definitely of interest, I'm quite familiar with the same anecdotal reports although off hand I don't know of hard evidence.

The MDAI derivative similarly sounds interesting, if it works the way we're assuming it does, I think it would be kind of sedating, dreamy, and euphoric? As an antidepressant I don't know, as a recreational drug, it might be to the taste of some.

We all know that SSRIs attenuate the effects of MDMA, so dose might need to go up, which is potentially problematic, although allegedly SSRIs have some protective effects against MDMA neurotoxicity. With all the MDMA derivatives I'd worry about potential serotonin syndrom lurking somewhere in the background.
 
I think part of why you don't see prodrug-and-releaser combinations in one molecule very much is because you need a lot more of the monoamine precursor to have a useful effect than 1 mol equivalent. For e.g. MDMA, with a molecular weight of 193 g/mol and 5HTP m.w. 220 g/mol that means a ~100mg MDMA dose would only produce about 114mg of 5HTP). I was under the impression 5HTP doses needed to be at least twice that for pre-loading.

I believe that focusing instead on high-protien (make sure its balanced in all the amino acids you need, or even better use multiple sources of protien...) snacks and meals is probably more useful all-around than focusing on any single neurotransmitter precursors. A snack of dried fruit, mixed nuts, and some pepperoni is much better tasting than a fistful of gelatin capsules full of broad beans, anyway. As a bonus, you are likely to get a bunch of other food based nutrients along for the ride, which is always good for recovery - and health in general.

I also have suspicions that stapling a rather quite polar 5HTP amino acid onto otherwise active compounds will affect PK and distribution, maybe negatively. The unmasked phenolic OH is especially concerning because it will probably be ionized in the duodenum - where drugs would normally otherwise assume an uncharged form. A charged drug cannot diffuse throguh the fatty cell membranes and as a result, will not be absorbed into the hepatitic portal vein. This means oral BA can be expected to be quite low. (c.f. morphine, 5-OH-DMT)

L-DOPA is even worse in terms of pharmacokinetics due to polarity. The double aromatic hydroxide aka catechol arrangement is super duper water soluble. The only reason L-DOPA can make it into the brain is through active transport. Peripherally administered IV dopamine is actually used in cases of... uh, something to do with the heart, I'm not a cardiologist. But it's used, all right. However, dopamine itself won't cross the BBB so pure DA injecions outside the brain don't have a reinforcing effect.

On the topic of "why lysine in lisdexamphetamine" - I can hear the audience asking that question :P
I suspect that lisdexamphetamine was the most promising amphetamine prodrug selected after a quick screening effort; there are after all only 20-some amino acids that are common. Having some lab guy plug dexedrine on a Merrifield resin and whack it a few times with all the amino acids they have in their storeroom, and feeding the resulting compounds to rats to see how they behave, seems to me exactly the sort of primary research that gets your name on a patent, and puts smiles on the executives who sign your paycheck. (That's just a guess, though... it would be nice, however, to read a story straight from the farm - so to speak...)
 
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Mephevanse would require a really high dosage though, like 500mg I'd say, and also wouldn't it be short lasting as well?

The chinese tried something like this with n-benzyl mephedrone, it was a flop for the exact reasons you stated (if meph was an order of magnitude more potent there might have been potential though)

N-(5,6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide
N-(5%2C6-methylenedioxyindan-2-yl)-(2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanamide.png

I really like this

The potential of MDAI as an antidepressant has always intrigued me despite my never having used the drug. I'd still be concerned about serotonin depletion though... Even with something as weak as MDAI it's still a pertinent concern... would a halogenated indanyl (remember 5-IAI?) be better?
 
I like these, but shouldn't the hydroxyl be in position #4 instead of #5? (or else a methoxy at 5)

Nevermind, I think I see your rationale. You're trying to get it to release 5-HTP.
 
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Sekio, I don't think the phenolic OH (pKa ≈10) would be deprotonated in the duodenum (pH 7-8.5). Anyway, I was meaning for pancreatic enzymes to break the amide bond. Once broken they follow respective pharmacokinetics of their parents.

Sekio, couple another molecule of 5HTP onto the protein chain if you want to release 2 molecules of HTP instead of 1 for every molecule of SRA?

I know you could just eat proteins, but I think it could be used as an anti abuse or sustainable mechanism.
 
Dresden, I double checked Wikipedia and the hydroxyl moiety is in the correct position for 5HTP release.
 
There are random, yet not so random molecules...
(which means synthetically not too far-fetched^, there are many other commerciallized meds with synth step harder than this)
This forum has keen eyes, i think ones like (eg. sekio) should be able to guess what these should be, they fit in some "requirements"*

(*in 2-D like plus my "imaginary" molecule simulation , I havnt tried 3D structure and minimize energy yet)

14478529501.png
 
There are random, yet not so random molecules...
(which means synthetically not too far-fetched^, there are many other commerciallized meds with synth step harder than this)
This forum has keen eyes, i think ones like (eg. sekio) should be able to guess what these should be, they fit in some "requirements"*

(*in 2-D like plus my "imaginary" molecule simulation , I havnt tried 3D structure and minimize energy yet)

14478529501.png

What are these molecules meant to do?
 
Trying to just heighten the electronegativity of cocaine by adding oxygens, but wonder why the likes of these two bonded tropane-3 position substituents aren't to be found (by me, at least) in the literature:

carbmethoxy:
YyGfE.jpg


acetoxy:
yCC4N.jpg


cyclopentane dioxy:
rZZrd.jpg


cubism:
UUo07.jpg


possible threat to the O-zone layer:
TQaki.jpg


EDIT:

Since there was a study that said co-ingestion of capsaicin containing foods with cocaine could be contraindicated and even fatal, I wonder if the opposite TRPM8 receptors, the cold sensitive ones that respond to menthol and the like, might be protective? Probably just absurd childlike reasoning on that one, but none the less, here's cocapulegone:

Hv8bB.jpg
 
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