While being consumed they will be converted into their active form, like psilocin-esters into psilocin. My ideas for substances which will undergo a heat-decarboxylation while smoked are:
1) alpha,N,N'-trimethyl-tryptophan. Synthesis e.g.: reductive alkylation with NaBH4 at pH >= 7 (to prevent beta-carboline formation) of tryptophan. Or: gramin + dimethylaminomalonates + NaOH.
2) alpha,N-dimethyl-phenylalanin. Synthesis: see my uncommented suggestion in phenylalanin -> amphetamine (maybe another ketone to prevent polymerization of the iminium?)

Let's talk about more substances, more mechanisms, their toxicology, their synthesis, their legal aspects...

Lilienthal
Member   posted 12-03-98 02:47 PM          
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 1) should have been N,N-dimethyl-tryptophan.
 
Lilienthal
Member   posted 12-03-98 02:52 PM          
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And some missing letters: e e e 
 
Beagle
Member   posted 12-03-98 03:25 PM          
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I like the idea of these prodrugs very much. The idea of converting the prodrug to the active cpd. during administration is appealing. For the tryptophan cpd you are suggesting, how would keeping pH of rxn >=7 prevent carboline formation? I understand that imine formation is best at ~6, but the reductive alkylation and the cyclization both go through imine intermediates, so no imine = no carboline = no alkylation, right? I once met a young chemist that had tried to alkylate tryptamine like this. Very pleased was he when he obtained beautiful white crystals. Very disapointed was he when it became apparent that as pretty as these xtals were, they were not the desired cpd.
 
drone 342
Member   posted 12-03-98 04:07 PM          
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I'm a little hesitant about alpha-alkylated amino acid prodrugs -- alpha-alkyl amino acids tend to have A LOT of various biolgical activity, those extra groups placed so lovingly are quite useful at deactivating a lot of different enzymes in the body -- meaning this stuff is hard-core medicinal shit with serious side-effects possible.
N-methyldopa *could* be kinda kewl, though (in an anti-parkinsonian way.) I'd like to personally bioassay 3,4,5-trimethoxyphenylalanine.

-drone #342

Lilienthal
Member   posted 12-04-98 02:05 PM          
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I've been in the wine-cellar and found some good vintages for you (or do we have to drink mead?).
Beagle: The Pictet-Spengler reaction (= beta-carboline formation from imine) proceeds via the iminium ion (4, 5). In the absence of acid (1) you can isolate the imines from tryptamine (or tryptophan) (2, 3). The pH optimum if working in aqueous conditions has to be tested, but aprotic solvents seem to be a better idea. I have no refs for the NaBH4 reductive alkylation in aprotic or alkaline solution. Could someone help me? If possible, this reaction would be the easiest and cheapest route to this (pro-) drug!

(1) J. Org. Chem. 49, 2699, 1984: Pictet-Spengler if imines in aprotic media only if traces of acid are present
(2) Anal. Chem. 45, 1536 1973: benzylidene-tryptamine
(3) Ann. Chem. 511, 1994: different imines from tryptamine
(4) J. Am. Chem. Soc. 29, 2864 1964: Pictet-Spengler reaction mechanism (short)
(5) Het. 33, 801 1992: Pictet-Spengler reaction mechanism (in detail)
(6) Anal. Chem. 40, 1910 1968: amino acid-ester-imines from bisulfite adducts (try to find the probable errors in this paper...)

Here are the refs for the gramine route (still very easy and cheap):

(7) Ann. Chim. (Rome) 48, 1037 1958: N,N-dimethyl-tryptophan from gramine + diethyl dimethylamino-malonate + NaOH or Ba(OH)2
(8) J. Med. Chem. 35, 1076 1992: diethyl dipropylamino-malonate from dipropylamine + Br-malonate
(9) Collect. Czech. Chem. Commun. 45, 92, 1980: dimethyl dimethylamino-malonate from dimethylamine + Br-malonate
(10) J. Chem. Soc. 547 1949: diethyl dimethylamino-malonate from dimethylamine + Br-malonate
(11) Org. Synth. Coll. Vol. I, 245 1941: ethyl Br-malonate from Br2 + malonate
(12) Russ. J. Org. Chem. (engl.) 30, 1042 1994: Br-malonates from Br2 + malonates

drone: Hey, it's a good idea to use the DOPA-decarboxylase for the conversion. Much SAR should exist on this field. I see, I have to go to the cellar. About toxicity: Some plants produce dimethyltryptophan and the alpha,N-dimethylphenylalanin isn't even synthetized. Their animal or human toxicology isn't explored yet. I think, enzymes handling Trp or Phe need the free alpha-C and/or the free amino group. But to be on the safer side, we may use the unnatural amino acid isomer. The enzymes ignore these amino acids (?), so they should also ignore their substituted analogues. Much work is waiting for us...

Cheers!

 
Lilienthal
Member   posted 12-16-98 01:33 PM          
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Here are the references for aprotic, non-acidic reductive aminations of tryptophan(ester) yielding N,N-dimethyltryptophan, the easiest and cheapest way to this substance. It's posted on the DMT BB: http://dmt.lycaeum.org/ncgi/Forum6/HTML/000006.html 
 
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