Stimulants of the Future

[EN21]

fascinating MAR

Sorry, I never heard about it, but I have an other question:
The closer I look at the MAR, the more surprising things catch my eyes:
Do I look right, if aminorex can be seen as a rigidisized PEA molecule and 4-MAR as the amphetamine (or even methamphetamine) counterpart. What nitrogen will be more basic and will interact with the receptor? (mind the possible tautomerisation) No idea, but to me it sounds reasonable. In that case it really would make sense to try further substituents at the aromatic moiety. (e.g.: methylendioxy- or 2,5-dimethoxy 4-any other thing, or even an indole). It could also be seen as an hydrolytic stable O-acetyl-norephedrine.
Just an other comment to the fluoroethyl substituents. Care should be taken, since most of fluoroethyl-containing compounds probably form fluoroacetic acid as a metabolite. It is highly toxic. For references see: http://www.fluoridealert.org/pesticides/fluoroacetic.acid.toxnet.htm
If the active dose of the drug is considerable low, this should not matter.

 

[Smyth]

Since the 2-thienyl heterocycle is considered the bioisosteric equivalent of a phenyl ring, im considering that this analog of amphetamine would be commerciably viable and worthy of exploration.

^^I know a guy who made some N-Et amp and said that it was much 'calmer' than meth although it did have somewhat attenuated potency. Also, I dont recall anyone ever mentioning alpha-ethyl-PEA although I personally have not got an interest in either of these two compounds.

 

[fastandbulbous]

Does anybody know N-Ethylamphetamin?Information appears extreme sparse on this one.

Oh yes! Many moons ago a friend & myself came into possession of 'a fair bit' of said compound and it is wasily on a par with amphetamine & methamphetamine in terms of abuse potential, CNS/locomotor stimulation etc. It's about on a par with amphetamine in terms of potency, but in terms of effect is a bit more like methamphetamine (probably due to octanol/water partition coefficient etc). It's longer lasting than amphetamine; more like meth, but doesn't seem to have anything like the potential of meth for driving people crazy etc.

Funnily, I remember reading at the time I had access to it that the S-isomer is metabolized (N-dealkylated to amphetamine) at a much slower rate than the R-isomer, so that might account for it's longer peroid of activity than amphetamine, but without doing to much to scramble the cognative processes like meth does.

It's one of those compounds I'd love to be able to come face to face with again, but sadly it was entered into the Misuse of Drugs Act about 14 years ago (Class C though!), so I don't think it's very likely

Since the 2-thienyl heterocycle is considered the bioisosteric equivalent of a phenyl ring, im considering that this analog of amphetamine would be commerciably viable and worthy of exploration.

For some reason, replacing the phenyl group with a 2-thienyl group produces compounds that are fairly poor locomotor stimulants - I can't remember the refs., but if you look you'll find them as they were in one of the 'big' journals

 

[yaesutom]

^^ Also there's N-propylamphetamine, N-ethyl is schedule 1 in the U.S. but the propyl analog isn't (well its an analog but thats it). A monkey on mars told me its weaker than amphetamine (i think 15mg N-propyl-A = 10mg amph. something like that anyway) and similar to the above posted for N-ethyl, smoother and longer lasting.

I found something interesting, there is this amphetamine pro-drug called Fenoproporex, its N-2-cyanoethylamphetamine, and I believe its schedule IV in the U.S., also found out, that its being put in some (well one particular brand seems to come up in many searches..) "herbal" weight loss products imported from brazil and sold in the U.S. . Easily found some of these places selling this herbal stuff by just googling fenoproporex. Wonder if its got any action before its metabolised into amphetamine?

Anyway I guess N-propyl-amphetamine would seem most interesting to get just 'cause its unscheduled.

 

[Church]

All I know is that if some of you chemists would get to making a euphoric, entactogenic amphetamine, one that doesn't necessarily cause the user to have epiphanies and psychospiritual revelations, I would pay top dollar for it.

Or, if there are still some chemists out there who aren't pussies about making drugs that are specifically controlled or illegal, would you please flood the markets with more MDA and less MDMA? Thank you.

MDA = the best recreational drug EVER!!!

 

[hussness]

Is there any general information available on how readily a certain type of acetyl group will get metabolized/hydrolized to the corresponding -OH? This is for those of you with a background in pharmacokinetics. I'm just curious because the acetyl group is ubiquitous in recreational substances.

 

[Smyth]

Yes, I have checked it out and there is not a lot of data on the subject, suggesting that it is simply a matter of common sense.

Bear in mind LAAM has an acetyl group so if the conditions are right, it can stay in-tact for quite some time.
But even upon hydrolysis, is the free-hydroxy is still able to maintain the compounds high activity?

Since MAM makes up quite a big percentage of heroin that has been kept in storage for any length of time, im guessing that the phenol position is suceptible to hydrolysis. Pka phenol = 10 vs. 16 for normal alcohol.

http://en.wikipedia.org/wiki/Psilocybin

Maybe this is a good place to consider what the relative effect of a phosphonate ester might have.

After that the order of ease of hydrolysis is primary>secondary>tertiary.

This is on the grounds of steric branching, whereas for the phenol it was an electronic effect.

http://en.wikipedia.org/wiki/3-quinuclidinyl_benzilate

See here in the above example how all the crazy steric bulk cuts out hydrolysis leading to a compound with a massively long half life even though esters are considered much more reactive than ethers. These bulked out phenyl groups are also present in LAAM. Also notice that although this is is a secondary alcohol, an ester is also composed of an acid portion. I know this is drifting off topic since your question was primarily concerned with the acetyl group. It does however show that steric bulking in both the alcohol and the acid elements can affect the kinetics of hydrolysis.

Classically we think of hydrolysis as an addition-elimination reaction and this mechanism is proven by radio-isotopic labelling experiments.

Since the reaction is bimolecular, steric crowding in the substrate around the reaction centre will block access of the water molecule (if acid catalysed) reducing the probability that a given trajectory will lead to a successful collision leading to formation of the reactive sp3 intermediate.

Also since the mechanism involves rehybridization from sp2 to sp3, the activation energy will be dependent on whether steric eclipsing is reduced/ increased in the intermediate relative to the reactant.

But then again this has its limitations. The free hydroxy in BZ gas would be difficult to esterify and even upon acetylation it would be readily hydrolyzed since it is energetically unstable. This is also a steric effect of there being excessive cramping, as oppose to lack of shielding.

With the two phenyl groups geminal to the tertiary hydroxy, im thinking that the reaction mechanism for hydrolysis might be elimination-addition, although this is just a theory.

I recommend u read this if u want further info: http://www.cem.msu.edu/~reusch/VirtualText/intro1.htm#contnt

While still using the original question as a spring board to look at other aspects of esters in drug molecules, see how it can be used as a time release mechanism in the following example:

http://en.wikipedia.org/wiki/Vanoxerine

 

[hugo24]

Ah,someone here had Ethamphetamin,who woulda have thought!
Just checked,yeah its also scheduled here.Hey wasn't that you who also tasted Ethcathinon (I think it lasted longer)?

Altough I read somewhere its a stimulant,the alpha-Ethyl-phenethylamin seems pretty inactive.T+0 20mg T+1h 20mg T+1.5h +40mg.feeling maybe something after it.T+2.5h +100mg.20' later I felt clearly the effects,heart beats faster (but the meter says only a miniscule increase 144/75 79).Maybe a peak at 4h,uneven heartbeat,152/86 64 the BP/PR values,stomach cramps,piloerection but no euphoria.Basically,just the physicals withouth any CNS effects.Taking more felt unsafe because of the heart irregularities.

 

[fastandbulbous]

^ Yeah, a friend who synthed some 1-phenyl-2-butylamine & it's N-methyl derivative said that they were rather disappointed with it in comparison with amphetamine. He did say though that the beta-keto analogues of alpha-ethyl PEA & the N-methyl compound were quite good CNS stimulants (he described the alpha-ethyl analogue of methcathinone as being almost as active as methcathinone).

Yeah, I've had N-ethylcathinone (the de-ethylated analogue of diethylpropion) a long time ago; it was pretty much on a par with methcathinone, but with less beta-adrenergic activity (pounding heart etc) as well - definitely a better CNS stimulant than diethylpropion

 

[hugo24]

That pretty fills the final holes on the close analogs of amp.
Again the bk's showing promise and a broader SAR profile.Pyrrolidino,para-fluoro,alpha dimethyl,valerophenon,n-propyl...

 

[vecktor]

legal analogues

if the purpose is to avoid the legal restrictions on the golden oldies then one might want to consider the prodrug derivatives of the various amines. Dihydronicotamide derivatives are very interesting as they are CNS specific, see the work of Bodor. In the mid 90's I identified other prodrug derivatives and routes to them not involving illegal precursors (in the UK) hint think isocyanates but my research was curtailed by the aptly named criminal justice system.
regards V

 

[snowblowjoe]

r u seriously going to say MDA is a better stimulant than 4-mar or pure crystal/glass?

 

[fastandbulbous]

if the purpose is to avoid the legal restrictions on the golden oldies then one might want to consider the prodrug derivatives of the various amines. Dihydronicotamide derivatives are very interesting as they are CNS specific, see the work of Bodor. In the mid 90's I identified other prodrug derivatives and routes to them not involving illegal precursors (in the UK) hint think isocyanates but my research was curtailed by the aptly named criminal justice system.
regards V

Never really considered them as viable CNS stimulants in terms of psychomotor stims as they have quite prominant convulsant activity (eg nikethamide) & that's something that's def best avoided for any drug.

Reuptake inhibitors seems to be the most promising area of research, it's just that there seems to be no hard & fast rule that distinguishes reuptake inhibitor drugs with very little stimulant effect from those with much more pronounced stimulant effects (see some of the WIN series vs cocaine)

 

[vecktor]

"Never really considered them as viable CNS stimulants in terms of psychomotor stims as they have quite prominant convulsant activity (eg nikethamide) & that's something that's def best avoided for any drug."

I perhaps wasn't clear, I am refering to making amide derivative of say amphetamine, or methamphetamine for example, using dihydronicotinic acid see patent US5525727

Basically the scheme works as follows, the amide is absorbed and crossed the BBB, non polar so easily done. once in the brain the dihydronictoinamide portion is oxidised to the fully aromatic nicotinamide derivative this is unable to cross the BBB as it is highly polar. the nicotinamide portion is then rapidly cleaved by esterase giving nicotinc acid and our desired amine ( methamphetamine or whatever).


As an aside this oxidation may be why LSD has extreme potency, LSD contains a dihydro pyridine ring, this can be oxidised to the pyridine which is highly polar and would not be able to cross back out of the brain through the BBB.

 

[fastandbulbous]

As an aside this oxidation may be why LSD has extreme potency

No it's because LSD is essintially a planar molecule due to the conjugated double bonds associated with the aromatic nucleus. 5HT2a agonists display maximal affinity for the receptor when the molecule is planar (eg DOB-dragonfly)

 

[mad_scientist]

Reuptake inhibitors seems to be the most promising area of research, it's just that there seems to be no hard & fast rule that distinguishes reuptake inhibitor drugs with very little stimulant effect from those with much more pronounced stimulant effects (see some of the WIN series vs cocaine)

In general, the abuse potential of dopamine reuptake inhibitors depends on how they affect the pattern of dopamine release and reuptake. Compounds that inhibit reuptake and also induce release of dopamine (such as methamphetamine or phenmetrazine), or compounds that inhibit reuptake but have no effect on release (such as cocaine, CFT, amineptine or methylphenidate) tend to be addictive drugs with potential for abuse in humans. On the other hand, compounds that inhibit reuptake but also inhibit release of dopamine (such as modafinil, mazindol, bupropion and vanoxerine) have mild stimulant effects and little abuse potential.

Note that vanoxerine (GBR12909) binds to the dopamine transporter 300x more strongly than cocaine but has little stimulant effect because it induces a mild and long lasting increase in dopamine levels quite different from the short and intense dopamine peak produced by cocaine. A similar pattern is seen with the drugs affecting serotonin reuptake; SSRIs like prozac or citalopram produce a mild and long lasting increase in serotonin levels but have little abuse potential, wheras drugs like MDMA and 4-methylaminorex produce a sudden and intense release of serotonin (and dopamine) which produces much more intense euphoria.

 

[Smyth]

SSRIs work in a different way to MDMA. Although they are both thought to affect serotonin, they work in different mechanisms. Im not sure that duration of action can be directly linked to addiction as such, although it does have a part to play in determining the 'rush' factor.

MDMA also affects, to a lesser extent, dopamine and noradrenaline, whereas SSRIs are much more specific in their action no serotonin.

Im thinking your theory is floored because that weould be like saying methadone has "little abuse potential" which clearly is of questionable validity.

The statement about vanorexine inhibiting dopamine release even though it is a potent DRI might be correct. I have seen this on Wikipedia. Quite simply I think people model the theory to fit the data. And when some new evidence emerges that doesnt fit the existing theory, a new one is postulated.

My view is that people take stimulants to get a surge in monoamines and that this is where the euphoria part comes from. Compounds that have a slow onset of action and are too 'lazy' fail int his regard. But this is not to say that compounds with a long duration of action or ones that are a bit slow off the starting blocks are not without their potential. I think that Indatraline may well have abuse potential which might be one of the reasons why it would not be a good candidate for cocaine addiction.

 

[mepat1111]

SSRIs work in a different way to MDMA. Although they are both thought to affect serotonin, they work in different mechanisms. Im not sure that duration of action can be directly linked to addiction as such, although it does have a part to play in determining the 'rush' factor.

MDMA also affects, to a lesser extent, dopamine and noradrenaline, whereas SSRIs are much more specific in their action no serotonin.

Im thinking your theory is floored because that weould be like saying methadone has "little abuse potential" which clearly is of questionable validity.

I may be wrong here as my knowledge here is limited, but I think he was trying to say that the abuse potential comes from the fact that MDMA induces the release of seratonin AS WELL AS inhibiting reuptake of seratonin. On the other hand, SSRIs only inhibite reuptake, meaning a gradual increase of seratonin levels, and less abuse potential. ie - the abuse potential comes from the combination of seratonin release and inhibiting the reuptake.

Also, would this be why it is so dangerous to take SSRIs with MDMA? As the seratonin released by MDMA would be already blocked for reuptake, increasing the effects greatly? I once met a guy who claimed he would sometimes take VERY small doses of MDMA while on anti-depressants (he had a script which he only used occasionally, apparently for phantom joint/muscle pain) - he did not know what exactly was the name of the chemical and the brand name was useless to tell it, but I assume it was an SSRI - and it would increase the effects greatly.

 

[Smyth]

Yes but MDMA is similar in structure to dopamine and also adrenaline. My theory is that at least to some extent MDMA goes into the brain where the body confuses it with endogenous monoamines, ie a 'scrambling' effect is experienced by the user.

Whereas SSRIs have a more targeted role to play and binding to the presynaptic 5HTT and isnt getting treated like a monoamine.

Ie MDMA is a monoamine mimic, as is amphetamine abd a host of other simple two carbon chain amines.

Although the therapeutic lag of antidepressants can be as long as several weeks, it actually starts inhibting the reuptake of 5HT as soon as the tablet is swallowed.

I personally actually can feel a strong effect from SSRIs even after one tablet. It's just that I dont think the mechanism of causing a sole increase in 5HT availability is someone that would make me happy. Combining a 5HTT reuptake inhibitor with a reliably self-administered doapminergic can even serve to attenuate drug seeking behavior according to some recent journals (last decade).

Plus it is not dangerous to combine an SSRI with MDMA. MDMA causes the 5HTT pump to work in reverse flooding the synpatic cleft with serotonin (this is according to scientific research not my own opinion). whereas 5HTT blockers are gonna stop transport in both directions presumably thereby 'blocking' the effect of MDMA.

 

[mad_scientist]

SSRIs block the reuptake transporter and so serotonin levels in the synapse rise, but this then activates autoinhibitory 5HT1B/1D receptors which limit further serotonin release. This, coupled with the long half-life of the SSRI in the body produces a subtle but long-lasting increase in serotonin.

MDMA on the other hand triggers the standard non-selective monoamine release of amphetamines in general, releasing increased amounts of dopamine, noradrenaline and serotonin by inducing vesicle trafficing. However it also reverses the 5HTT serotonin transporter and so releases serotonin by a second seperate mechanism, hence why MDMA releases much larger amounts of serotonin than most amphetamines. The half-life of MDMA is however fairly short, also it uses up most of the pool of serotonin in the neuron quite quickly and so its action tends to be self-limiting unless there is extra 5HTP avaliable to make fresh serotonin from.

Pretreatment with SSRIs blocks the effects of MDMA by preventing it from entering the neuron through the 5HTT (and hence stopping the MDMA from reaching either of its two targets inside the cell). However if you take an SSRI just as the MDMA is starting to wear off, it can indeed block the reuptake of the serotonin the MDMA has dumped in your brain and make the serotonin peak last much longer - unfortunately this is not generally pleasent though as the serotonin receptors start to get desensitised, so the positive effects from the MDMA wear off and just leaves a hot, sweaty, nauseous, anorexic too-much serotonin feeling, which can last for days. So I guess there could be some risk of serotonin syndrome etc if SSRIs and MDMA were combined in a high dose, especially if 5HTP were taken as well.