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Stimulants of the Future

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Subjectively, diethylpropion seems to supress appetite by producing butterflies in the stomach (it's not subtle, by any means). Ethcathinone was smoother (didn't seem to come on any quicker), but still a bit rough around the edges; think it's because one of the metabolic routes reduces the keto group to an alcohol and voila, you've got an ephedrine derivative (barely supresses wretch at thought of ephedrine!)

Tranylcypromine isn't an alkylator as the three carbon atoms don't have much in the way of charge separation going on, hence fairly stable (well stable compared with most three membered ring structures). Replace one of the carbons with a heteroatom like nitrogen or oxygen, and you've got a fairly pronounced case of charge separation, making the ring a lot more susceptable to ring opening via addition reaction (a bit like addition reactions to alkenes, but a lot more pronounced)

The 3-benzylmorpholine sequence:

phenylalaninol + 2-iodoethanol = 3-phenyl-2-(2-hydroxyethylamino)propanol

then ring closure via dehydration using conc sulphuric acid (or similar strong dehydrating agent). Removes water from two hydroxyl groups to form an ether; in this case, morpholine being a sort of cyclic ether. Instead of using 2-iodoethanol, you can use ethylene oxide, but it's a bit more difficult to work with.

You could start from phenylalaninol, but it rather defeats the simplicity of starting from an amino acid. I do share your feelings about lithium aluminium hydride though (and sodium hydride, sodamide etc...). Nasty little buggers.

One last thing; nobody's mentioned alpha,beta-dimethylphenethylamine (3-phenyl-2-butylamine) and it's N-methyl deriv. They're fairly effective, uncontrolled (at least in UK) and for anybody going to the bother of synthesising benzyl methyl ketone (BMK, phenylacetone) for amphetamine synthesis, it's exactly the same route, but instead of starting with phenylacetic acid (which is watched), you start with 2-phenylpropionic acid (which isn't). You could even get away with starting from 2-phenylpropionitrile (1-phenethyl methyl ketone might be seen as taking the piss, as anything even slightly like benzyl methyl ketone had chance to be kept note of, if not activly watched)
 
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Well LiAlH4 does not have to be used under a nitrogen atmosphere in the same way that BuLi must be used under Schlenk line. I am not saying that I like using it because it does have associated risks. However from a synthetic standpoint they are literal god-sends. How do you reduce an ester without LiAlH4?

Back to the job at hand. Yes, why reduce it yourself when you can actually buy phenylalaninol. Uh ive been looking at Sigma & its not cheap! Cost does have the propensity to affect things, undoubtedly. Plus the morpholone ring forming reaction looks difficult, I bet that cant be high yielding. Also these products are all phenethylamines. Technically atleast they are all illegal.
 
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Plus the morpholone ring forming reaction looks difficult, I bet that cant be high yielding. Also these products are all phenethylamines. Technically atleast they are all illegal.

The ring closure using conc sulphuric acid is both easy and high yielding (hunt down phenmetrazine synth and you'll see). Basically it involves a two hour reflux and voila, ring closeure to a morpholine

Also, how do you think that they are illegal? Unlike the US, with it's controlled substance analogue act, here in the UK for a chemical to be controlled, it either has to be specifically named, or covered by one of the coverall paragraphs for Class A drugs. Psychedelic phenethylamines have a coverall paragraph, but even in that case, the had to add some named compounds from PIHKAL, because of how specific that part of the act is; as far as phenethylamine derived stimulants go, there is no coverall paragraph, so if it's not specifically named, it's not controlled. The only controlled stimulants named that contain a morpholine ring are phenmetrazine and phendimetrazine
 
^^ nope, just the ones that fall under the tryptamine and phenethylamine derivatives paragraphs (I'll stop using coverall, as they obviously don't), and they're just for psychedelics. The scope for straight stimulant compounds is wide open (until they decide to concentrate on them!)


As far as the synthetic chemistry goes, I hung up my leibig a long time ago, due to LE visits, galloping paranoia and most importantly, I promised my other half I would before we got hitched. Getting a promise out of me is like pulling teeth, mostly because if I do give my word, it's because it's an absolute on my behalf.

Doesn't stop me passing on what knowledge I gained beforehand though (plant extractions not coming under synthesis either!)

BTW Racemic-SYN-4-(3,4-dichlorophenyl)-3-carboxymethyl-methylpiperidine SUX!

Actually, it sounds like it would have potential as an antidepressant a la amineptine, which, from what I've read, is rather pleasant
 
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I have a recent article on ritalin SAR's (2001). In this particular article the focus was on exploring heterocyclic rings other than piperidine. Neither morpholine nor any of the other ring sizes threw-up any suprises. But, I understand (from what I have read on BL) that for ritalin the benzylic -CO2Me is easily metabolized off. In fact I thought it was due to this reason that it is short-acting.

I have got a backup file for the document that was in the 'Novel Discourse' section of the hive from a few months ago. From the discussion there I gathered that the morpholine ring is the most potent in its class, more so even than the corresponding piperidine compound.

Looking back at this, it was the diphenylalaninol that this was based on, phenylalanine derived molecule was merely hypothetical. It is no suprise for me that swapping the CO2Me in ritalin for a benzene would give a fully active compound with a lowered 'buzz' potential that is long lasting.

But this business of the morpholine ring being more active than the piperidine ring is confusing to say the least. Please explain..
 
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It's me again!

The bit you took from the Novel Discourse was actually the bits that I posted; they were a sort of condensed down verson of some of the research I did while doing my M.Sc. (SAR of anorectic agents). As for why the morpholine ring is more potent than the piperidine ring, I haven't a clue; as they are not anorectic agents, so my delving into their action came to a halt at that point.

PS hydrolysis of the methyl ester group is the main metabolic route for deactivation in man. Replacing the carboxymethyl group with a straight acetyl group (to give a ketone) might work to extend activity - it works for opiates (hydroxypethedine vs ketobemidone)


Oh one other thing that I found after grubbing through my old stuff:

O-acetylephedrine is quite a potent stimulant (and appetite supressant) that is free of all the nasty, shitty peripheral effects of ephedrine. The only drawback is that it's unstable, and if it encounters an alkaline enviroment, the acetyl group transfers from the oxygen atom to the nitrogen atom.

It's potency though, is due to masking the polar OH group by esterification with acetic acid. Just a thought, but O-methylephedrine might well be a potent stimulant for the same reason (and easy to produce, and stable: treat ephedrine with a strong base like sodium hydride or sodamide, then add a molar equivalent of methyl iodide and voila)

Anybody ever seen anything about O-methyl ephedrine or phenylpropanolamine?
 
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Riemann, my problem with that comparison was that no one seems to experience any MDxx-like affects from fenfluramine or dextrofenfluramine (at least to my knowledge). D-amp. releases NA and DA, as do most amps, but it was my understanding this contributes mainly to the stimulant (speed) effects). Therefore, I'm making an assumption here: the 5-HT release it likely to be responsible for the 'trippiness' of MDxx compounds. But if this is the case, then I'd expect dextrofenfluramine and/or fenfluramine to have similar 'trippy' effects, but to my knowledge, they don't. Maybe they (dextrofen. and fen.) don't have the same affinity for the 5-HT2a receptor, which you say "contribute to their [MDxx compounds] 'trippiness.'"

MDxx compounds don't have much of an affinity for the 5HT2A receptor (compounds that do produce the classic psychedelic experience, as opposed to the entactogen effects (empathy, abolition of anxiety etc) that MDxx compounds produce). They do cause a huge efflux of serotonin from pre-synaptic storage vesicles, which will interact with all of the 5HT receptors to some degree.

The difference between MDxx compounds and dexfenfluramine is that MDxx compounds also have quite a large effect on dopaminergic neurones as well as serotonogic ones, whereas dexfenfluramine acts almost exclusivly through serotonogic mechanisms. To that extent, it is most probably quite like comounds like 3-methoxy-4-methylamphetamine and 5,6-methylenedioxy-2-aminoindan. IAP has more dopaminergic activity than those two, but it's still a long way from MDA like activity. IAP and amphetamine together do produce quite a pronounced MDA like activity, but I wouldn't even consider mixing dexfenfluramine with amphetamine due to reported cases of pulmonary hypertension.
 
Granted, combination of (d)-fenfluramine and (d)-amphetamine would not be very wise due to pulmonary hypertension and/or arrhythmias / torrsades de pointes (sp?) danger. From a purely theoretical standpoint, however, I think we are making the same point--the effect of MDxA compounds is mainly due to massive 5-HT and DA (and NA, the poor neglected bastard stepbrother of DA :)) release. Since (d)-fenfluramine releases only 5-HT and (d)-amphetamine releases NA and DA, I bet they would feel similar. However, that is kind of tangential to the 'Stimulants of the Future' title, so sorry for drudging it back up.
 
Another tangent to off-topic subjects

I just had a thought about modification of stimulant skeletons that might open up an interesting side topic. The entactogen drugs originally came from modification of a stimulant drug (amphetamine) by sticking a methylenedioxy group onto the phenyl ring, but there are another group of modifications that produce drugs with entactogen activity, but have never found wisespread use due to their neurotoxicity; namely the 4-haloamphetamines and N-methyl derivatives.

I've read mixed things about 4-fluoroamphetamine, but in things like the 4-halo 2C-X compounds, the fluorine derivative isn't really representitive of the other halogens (2C-C, 2C-B & 2C-I). Equally, 4-bromoamphetamine, 4-iodoamphetamine and the N-methyl derivatives seem to have profiles a lot more like that of MDA/MDMA than 4-fluoroamphetamine, but are quite neurotoxic in all studies.

Developing an idea I had regarding the 2-fluoroethyl group as a replacement for bromine in 2C-B to give 2C-EF as a possible, non-scheduled (in the US, at least, if not the UK) equivalent to 2C-B, I wonder what sort of properties 4-(2-fluoroethyl)amphetamine and 4-(2-fluoroethyl)methamphetamine would have. The 2-fluoroethyl group is a pseudohalogen, in that it has the same effect on the electronic configuration of the aromatic ring, as say a bromo or iodo group. So by extension, I would guess that 4-(2-fluoroethyl)amphetamine and 4-(2-fluoroethyl)methamphetamine would have a similar pharmacology w.r.t. 5HT and dopamine as 4-bromoamphetamine/4-bromomethamphetamine, but becase of differences in the size of the group etc., could possibly not be neurotoxic. This would lead to a couple of new serotonogic, entactogen drugs without the methylenedioxy ring (which would be a gift to clandestine synthetic chemists - no reliance on safrole). From what I remember from studies in rats, the 4-bromo derivatives are 3x the potency of MDMA in their effects on 5HT and dopamine.

Mind you, it's also possible that 4-fluoroethylamphetamine might turn out to be as neurotoxic in humans as well, or as equally dangerous as 4-methylthioamphetamine (MTA) because of MAOI activity; so any refs or info regarding 4-chloro/bromo/iodo amphetamine/methamphetamine pharmacology would be appreciated (I very much doubt if there is anything out there about 4-(2-fluoroethyl)amphetamine, other than a possible synthesis).

I know it's a bit of a long shot, but unlike the psychedelics and stimulants, there aren't many drugs out there that are primarily entactogens. We definitly need more of them to choose from/work with
 
Beyond the 4-fluoro analogue, para-halo substituted amphetamines seem to have a high selectivity for 5-HT release and also seem to cause 5-HT neurotoxicity. This seems to be the case for any electron-withdrawing moiety in the 4- position, such as -OMe (PMA), -SMe (4-MTA), etc... For example, para-chloroamphetamine (PCA) is used to ablate 5-HT neurons in experimental animals. I assume that 4-bromoamphetamine and 4-iodoamphetamine are similar to PCA--neurotoxic 5-HT releasers.

N-alkylation adds a new dimension to the picture, however. Phenomenological reports (one on this sight in Trip Reports, I believe) have shown that 4-methoxy-N-ethyl-amphetamine (PMEA) has an empathogenic-like effect. Studies have also shown that N-alkylation reduces the toxicity of 4-methoxy substituted amphetamines, rendering PMMA less toxic than PMA and PMEA less toxic than PMMA. Based upon this, 4-bromo-N-ethyl-amphetamine (PBEA) might be a really interesting compound. In fact, an old (and I mean old), study demonstrated a cross-tolerance between 4-bromo-N-methyl-amphetamine (PBMA) and LSD:

Knoll J, Vizi ES (1970). Cross-tolerance between para-bromo-methamphetamine (V-111) and LSD-25. Pharmacology. 4: 278-86.

I wonder if this cross-tolerance would extend to MDMA? Also, your point about MDMA having both stimulant and empathogenic effects is an interesting one. Can the two psychical effects be teased apart? A number of people assume that MDEA (Eve) is more of a pure empathogen and less of a stimulant than MDMA or MDA. I wonder if this is true? MDEA is more selective for 5-HT release than MDMA, if I recall correctly.

In addition, if one wanted a true empathogen, modification of the vesopressin/oxytocin peptidergic system would add to the effect of a serotonergic amphetamine.
 
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Beyond the 4-fluoro analogue, para-halo substituted amphetamines seem to have a high selectivity for 5-HT release and also seem to cause 5-HT neurotoxicity. This seems to be the case for any electron-withdrawing moiety in the 4- position, such as -OMe (PMA), -SMe (4-MTA), etc... .

I wasn't aware that any studies have documented neurotoxicity of PMA and MTA. I know PMA is cardiotoxic, but that's got more to do with adrenergic stimulation; MTA was originally claimed to be a non-neurotoxic MDMA like agent, it's just that in vivo, MTA is an MAOI, and the overall toxicity is linked to serotonin syndrome produced because of the MAOI activity.

That's why I thought 4-(2-fluoroethyl)amphetamine might turn out to be a useful entactogen (barring it having MAOI activity - the cardiotoxic effects of PMA seem to be directly linked to the 4-methoxy group, and the fact that an oxygen atom on the 4 position confers all sorts of adrenergic activity)
 
I finally tossed my copy of PIHKAL a coupke of months back. I think I recall seeing something similar to this there (DOEF or some such compound). Slight road-block may lie in the availabilty/cost of starting materials. But I agree sort of that it might be an idea.
 
I don't know if this is in any way related to bydrobromide's question, but are there any modifications that could be made that would have any of the following effects: increased potency, different duration of action/half life (both longer and shorter), increased euphoria (not sure you can answer this without any type of experiment/actual usage...but if it is possible to determine, I'm sure some of the bright minds on here could do it).

I just wanted to point out that the title, "Stimulants of the Future" may not be the best title for this thread...as I'm really not concerned about what are the most probable stimulants that we will see in the future. Rather, I'm looking for any possible stimulants, regardless of difficulty of synthesis or even ones that would NEVER be made (due to whatever circumstances would prevent them from being made). Ideally, I'd like to know the "most euphoric" possible stimulants, regardless of anything that would prohibit them from being made (i.e. difficulty of synthesis, difficulty obtaining precursors, illegality, etc.). Just wanted to make that clarification.
 
That really depends on your definition of 'psychostimulant.' If you mean "a compound that keeps one awake," then the di-chloromodafinil compound that I suggested might have the greatest potential. If you mean "a compound that causes a 'euphoric' rush" then I don't know if anything more 'euphoric' than (d)-methylamphetamine can be made. However, what do you mean by 'euphoria,' as that term has different meanings to different people. Some people think that (d)-amphetamines are the most euphoric compounds out there, due to the mental clarity and 'rush' engendered by them. Others prefer a more serotonergic amphetamine, such as MDMA, with its empathogenic feelings of 'romantic or spiritual love.' Others seem to prefer the quick up/down effects of cocaine and methylphenidate, in which case, dichloromethylphenidate has the greatest potential.

With respect to the 4-hydroxyl derivatives of methamphetamine and methylcathinone, I don't think that a 4-hydroxyl derivative would be lipophilic enough to cross the BBB. Perhaps a 4-halo derivative of methylcathinone would be interesting.
 
Riemann Zeta said:
With respect to the 4-hydroxyl derivatives of methamphetamine and methylcathinone, I don't think that a 4-hydroxyl derivative would be lipophilic enough to cross the BBB. Perhaps a 4-halo derivative of methylcathinone would be interesting.
Click to expand...

The reason I asked was I found some information on 4-hydroxy-methamphetamine, specifically saying that it was an active metabolite of methamphetamine. How active, and whether or not it would even be worth it to experiement with is beyond me...
 
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If the hydroxy group is added after crossing the NNN, then it will have some central effects; if it's metabolized outside the BBB, then the effects it will have will be the same as stimulation of the sympathetic NS (increased heartbeat, dry mouth etc)
 
Presumably he hit the wrong key by accident.

Wrt to dichlororitalin, I have a patent where the nitrogen atom becomes an oxygen atom. The starting material used is thus tetrahydrofuran. I'll post details in a little while.
 
i would like to see an mdma 4-methylaminorex hybrid (you could call it MDAX) also, if you can find a mirror of the old rhodium site there was a great pdf dealing with cocaine analogs.
 
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