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Prodrugs for d-amphetamine. N-OH? N-?

Y

yoyoman

Bluelighter
Joined
Jun 11, 2006
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320
I'm looking to find out what you can stick on that nitrogen that would get cleaved off fast and be light enough to make it nearly (as close as possible) identical to d-amphetamine. But, be different enough to where it doesn't seem as shady having some around. (R)-N-OH-1-phenylpropan-2-amine (like N-OH-MDMA or FLEA) phosphate salt (rather than sulfate just to be different, citrate or acetate whatever works that's not too heavy).. but that might be bad because some of it would degrade to d-amph?

What other (light) things can you stick on there that are unlikely to degrade to d-amphetamine immediately (keeping it "more legal")? Probably all sorts of stuff.. but the lighter the better so the potency's aren't too off. Something bigger than a N-OH but not quite something like l-lysine.. Something that would get cleaved off pretty fast but also acceptable if it takes time making it a d-amph prodrug but quicker acting than something like Vyvanse.


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Also I posted this in the sticky thread for the not quite advanced discussion regarding my ChemBioDraw/Office i'm confused about:

http://www.bluelight.ru/vb/threads/...-More-Thread?p=9945228&viewfull=1#post9945228
 
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really? i wasn't asking for ANY synthesis discussion at all, just what kinds of N-substitutions could be put on there, thats all. I edited my post and took out some stuff just now.

Also hope someone knows why when I visually vertically flip a molecule in ChemBioDraw (and have it set to auto-update name) it changes from (S) to (R) even though the molecule is identical. Like, looking at it upside down. I think I have screwed up the installation or something.
 
NeighborhoodThreat said:
This is bordering on what we don't allow here.
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I dunno, as far as I can tell there's really nothing about synthesis. He's asking what you could put on the molecule, not how.

FWIW, I don't think many amide substituents would be easily cleaved. After all, amides aren't very reactive, they're the most stable carboxylic acid derivative save for the carboxylate anion. Although I must say that my knowledge regarding biological systems is sorely lacking compared to many on this board, so I'm not sure what may be possible due to enzymatic catalysis.

The reason that vyvanse is effective is because it exploits the presence of endopeptidases in the gut, which provide ideal conditions for the peptide cleavage to take place. Technically you could use different amino acids, and they would all probably work (the only thing that would change is the specific enzyme that performs the cleavage, depending on what "kind" of amino acid it is, eg. nonpolar; polar, uncharged; charged)
 
Roger&Me said:
FWIW, I don't think many amide substituents would be easily cleaved. After all, amides aren't very reactive, they're the most stable carboxylic acid derivative save for the carboxylate anion. Although I must say that my knowledge regarding biological systems is sorely lacking compared to many on this board, so I'm not sure what may be possible due to enzymatic catalysis.
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an amide is a component of a peptide bond, so what is stable in the laboratory is not necessarily stable in vivo
 
Roger&Me said:
I dunno, as far as I can tell there's really nothing about synthesis. He's asking what you could put on the molecule, not how.

FWIW, I don't think many amide substituents would be easily cleaved. After all, amides aren't very reactive, they're the most stable carboxylic acid derivative save for the carboxylate anion. Although I must say that my knowledge regarding biological systems is sorely lacking compared to many on this board, so I'm not sure what may be possible due to enzymatic catalysis.

The reason that vyvanse is effective is because it exploits the presence of endopeptidases in the gut, which provide ideal conditions for the peptide cleavage to take place. Technically you could use different amino acids, and they would all probably work (the only thing that would change is the specific enzyme that performs the cleavage, depending on what "kind" of amino acid it is, eg. nonpolar; polar, uncharged; charged)
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Indeed. The part about a Chinese lab reading this for legal reasons is a bit dodgy though ;)
 
Any other substitution somewhere other than the nitrogen, such as 2-fluoroamphetamine (I heard good things but that it has a ceiling effect) are never as good as the real deal. I'm curious about 2-fluoromethamphetamine after hearing such good things about 2-FA. But anyway that's kind of off the topic.

Also are both d-amph and d-methamp both the (R) versions? If I add anything to the nitrogen it switches to an (S). So would (S)-N-(1-phenylpropan-2-yl)hydroxylamine = N-hydroxy-dextroamphetamine? (the good stuff). Some websites say that d-methamp = (S)-N-methyl-1-phenylpropan-2-amine (while others say its still (R) ). Where as the unsubstituted nitrogen (dextroamphetamine) is (R)-1-phenylpropan-2-amine.

I guess in this case, its just easier to say dextro or levo if the R/S thing complicates things a bit. Dextro is the good stuff, Levo is mostly PNS (generally speaking although i've had decent racemic amp before)

--- edit: Neighborhoodthreat you make a good point, maybe i should have posted this on a different chem site.. but i doubt for some reason any of this would show up as RC's. But I forgot about the fact that *some* come here to get info like this.
 
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This discussion doesn't currently run particularly close to touching on synthesis.

Also are both d-amph and d-methamp both the (R) versions? If I add anything to the nitrogen it switches to an (S). So would (S)-N-(1-phenylpropan-2-yl)hydroxylamine = N-hydroxy-dextroamphetamine? (the good stuff). Some websites say that d-methamp = (S)-N-methyl-1-phenylpropan-2-amine (while others say its still (R) ). Where as the unsubstituted nitrogen (dextroamphetamine) is (R)-1-phenylpropan-2-amine.
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This is a bit beyond my knowledge, but are you sure that the R/S nomenclature refers to the same chiral center in the case of heavy nitrogen substitutions? The whole argument doesn't make much sense to me, as I don't see how a nitrogen substitution would change chirality about the alpha chain. Also, for either amp or meth, the S isomer (in this case, also the dextro isomer) is the most active.

ebola
 
(stupid img button!) see the wikipedia articles for these:

220px-Clobenzorex_structure.svg.png
clobenzorex

Benzphetamine.png
benzphetamine

220px-Amphetaminil_Structural_Formulae.png
amphetaminil

I have a curiosity about this entity, which I believe would be hydrolyzed into GHB and amp:
MoleculeMol.ashx
 
Carbamate prodrugs of phenylethylamines: a neurochemical investigation
Carbamate prodrugs of phenylethylamines: a neurochemical investigation. Baker, G. B.; Coutts, R.Several substances are used for example 93528-35-9 which is its cas registry number. T.; Nazarali, A. J.; Danielson, T. J.; Rubens, M. (Dep. Psychiatry, Univ. Alberta, Edmonton, AB T6G 2G3, Can.). Proc. West. Pharmacol. Soc., 27, 523-5 (English) 1984. CODEN: PWPSA8. ISSN: 0083-8969. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Following i.p. administration of the carbamate prodrugs N-ethoxycarbonylamphetamine (I) [93528-35-9] and N-ethoxycarbonyltranylcypromine (II) [91640-64-1], both at 0.1 mmole/kg to rats, the brain levels of the free drugs amphetamine [300-62-9] and tranylcypromine [155-09-9] were 9.95 and 8.95 nmole/g, resp., 1 h after the drug administration; the resp. levels of I and II in the brain were 4.15 and 4.83 nmole/g. One h after i.p. injection of 0.5 mmole N-ethoxycarbonylphenylethylamine (III) [6970-83-8] to rats, the resp. brain levels of III and phenylethylamine [64-04-0] were 15.6 nmoles/g and 190 pmoles/g; when PEA-HCl (0.5 mmole) was injected, 835 pmoles PEA/g was found in the brain. II injection inhibited brain MAO [9001-66-5]-A and -B by 79.1 and 93.4%, resp. In vitro, II at concns. equiv. to the levels of tranylcypromine found in vivo, caused 11.7% inhibition of MAO-A and no inhibition of MAO-B; tranylcypromine caused 83.9 and 99.0% inhibition, resp. Thus, it appears that the MAO inhibiting activity of II in vivo is due to the tranylcypromine formed from the prodrug. Apparently, carbamate analogs are useful prodrugs of bioactive amines. .
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So from what i gather, this wouldn't degrade easily (like N-OH would) but would still work in the body. Not sure how fast its cleaved off though. Interesting
 
FWIW I think that amphetamine and methamphetamine oximes are still active as transporter inhibitors. The heavier alkyl substituents also confer a greater affinity for NE release over dopamine. Potency for N-alkyl groups is something like methyl > ethyl = hydrogen > oxime > propyl >> butyl, probably because heavier alkyl substituents are harder to take off metabolically.

I know that the bigger aryl and benzyl substituents are much less active at monoamine transporters and may just be prodrugs for the primary amine.

The best options for prodrugs have already been covered (amide link like Vyvanase, carbamate ester). I don't expect the oximes to be very useful. Amphetamine hydrazide would be a deadly MAOI, alkyl and aryl subs have been done to death, and N-oxides and oximes are unstable or less potent than the parent compound.
 
I second that on the hydrazide.

Hydrazines are NOT things in general that should go into the body. Many are extremely toxic (such as hydrazine itself, the highly toxic monomethylhydrazine that is released by the deadly fungi known as false morels, sometimes consumed after careful cooking, involving boiling multiple times throwing away the water each time prior to cooking to eat...even then the fumes have killed cooks and sickened people in cars transporting the mushrooms, that actually never ate a single bite)

And a fair few hydrazines with similar phenalkylamine backbones are MAOIs as stated. Irreversible ones, given the reactivity of the hydrazide. Phenelzine is such an example. Pretty dangerous, compared to the competitive MAOIs inhibiting MAO-a such as moclobemide and harmala alkaloids. Eat a pot noodle (forgetting the soy derivatives in there being fermented and potential tyramine source, added soy sauce, two pot noodles after a harmaline/harmine and DMT combination) on harmala, and I was fine. If I had done that on phenelzine I would quite possibly have ended up in hospital with a hypertensive crisis, or worse.

Has anyone any examples of a carbamate prodrug for an amphetamine of any kind? thats something I've been looking into bioassay myself, and I'd love to hear of any examples of it having been done.

A hydrazide of amphetamine? oh...great...lovely. Irreversible MAOI AND the very class of drug, a multiple monoamine releaser/reuptake inhibitor, that is most contraindicated, and highly dangerous, if not lethal, with MAOIs, all rolled into one.

Good way to painfully exterminate a speed freak who is your worst enemy, but thats about the only use, save possibly as in vitro research agent, for that particular compound.
 
regarding amphetanil.
this was available for a longtime in germany as a pharmaproduct.
AN 1 was the name,10mg amphetanil per tablet.
1 or 2 of them gave you a clean strong amphetamine push after aprox.1 hour.
the drug lore says to take it with a little alcohol to help the tranformation to amphetamine(I always did).
this means also very little spontanous redosing/no insufflication.
it was taken of the market, not because any problems with the drugs action,but the drug run on a very old licence.
the compony could have gotten a new licence,but to run all tests etc. is expensive and amphetanil is old/patentfree,
they opted not to do.also the indication narrowed down to ADHS.
it started with "lack of motivation(especially in elderly)","lack of libido","tiredness" et. cetera.
this was my favorite pharm,still miss it.
 
Pro-drugs are kinda hit or miss, you really have to test them (preferrably on an animal first and not you) to find out how fast they cleave, its hard to predict. My first guess would be to go with methyl or ethyl carbamate as has been suggested, but not any N-OH. Oximes don't convert to the N-H readily, its usually the other way around. They can also be carcinogenic. be careful what you're putting in your body man :)
 
Limpet_Chicken said:
Has anyone any examples of a carbamate prodrug for an amphetamine of any kind? thats something I've been looking into bioassay myself, and I'd love to hear of any examples of it having been done.
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How about cloforex?

The cyclohexylmethylcarbamate of amphetamine is intriguing, but it might be toxic as fuck. The corresponding carbonate ester is well known from steroids, e.g. trenbolone, but the carbamate could be very different in terms of toxicity.
 
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Roger&Me said:
I dunno, as far as I can tell there's really nothing about synthesis. He's asking what you could put on the molecule, not how.

FWIW, I don't think many amide substituents would be easily cleaved. After all, amides aren't very reactive, they're the most stable carboxylic acid derivative save for the carboxylate anion. Although I must say that my knowledge regarding biological systems is sorely lacking compared to many on this board, so I'm not sure what may be possible due to enzymatic catalysis.

The reason that vyvanse is effective is because it exploits the presence of endopeptidases in the gut, which provide ideal conditions for the peptide cleavage to take place. Technically you could use different amino acids, and they would all probably work (the only thing that would change is the specific enzyme that performs the cleavage, depending on what "kind" of amino acid it is, eg. nonpolar; polar, uncharged; charged)
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^^^ common but incorrect urban legend. It is converted in the blood by enzymes attached to red blood cells. 0% is converted in the gut. References available upon request.

Attaching a peptide that does get cleaved in the gut would most certainly speed up the onset of action compared to lisdexamfetamine.
 
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