⫸STICKY⫷ I Like to Draw Pictures of Random Molecules

Hodor

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Would it be possible to make simple pro-drugs like esters from gabapentinoids such as pregabalin? For example an N-ethyl ester similar to theanine or a nicotinoyl-ester similar to picamilon.
There is no such thing as an "N-ethyl ester". Condensation of an acid with an amine forms an amide.

Could those inositol-esters make sense as a pro-drug?
Why inositol of all things, though? Inositol has a greater molar mass than pregabalin itself, and it is hydrophilic as hell, so its bioavailability might actually be worse.

(Pregabaline is at the moment just a normal-prescription medicine and no narcotic/very controlled substance so the esters would be legal in most countries, also it's quite cheap and easy to produce and has massive recreational potential and gained a lot of popularity over the last years, why not making RC-analogues of gabapentinoids, at least they're a class of drugs with relative low toxicity and huge medicinal and recreational windows/safety).
Compared to benzodiazepines, pregabalin's recreational potential is far lower. Also, one of the problems with gabapentinoids is that their structure-activity-relationship is still not all that well-understood. Gabapentinoids apparently need to be actively transported into the brain via special amino acid carrier proteins. For years, the search for a successor to pregabalin has been slowed down by the fact that compounds that seemed much more potent in the in-vitro binding assays showed little if any increase in in-vivo potency, as their structural modifications would also decrease affinity for the aforementioned amino acid carriers, no longer justifying the significantly more complex synthesis.
 
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Hodor

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Edit: Haha, just as I drew those morpholine-phenidates in one of my last posts it is suddenly available as a research chemical, synchronicities can be quite nice sometimes.
"Methylmorphenate" (i.e. methylphenidate with the piperidine ring replaced by morpholine) briefly appeared on the RC market in 2015. The reason its appearance was rather brief was because it was barely active, at only about 1/10th the potency of its parent compound.
http://www.bluelight.org/vb/threads/766592-Novel-stimulant-Methylmorphenate
 

Soulfake

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@hodor

There is no such thing as an "N-ethyl ester". Condensation of an acid with an amine forms an amide.
Thx, I got that wrong. Somehow I had in mind that theanine was an ethyl-ester but it's an ethylamide analogue of glutamine. Do esters and amides behave similar in some ways? As far as I have seen/read both esters and amides often hydrolize in the body, depending on the molecule structure more or less fast while I guess most esters do hydrolize quicker than amides (I'm just a layman in chemistry and don't have real knowledge about basic and complex stuff, just a few pieces of information I read over the last 10 years about rc's and substances in general.)

Why inositol of all things, though? Inositol has a greater molar mass than pregabalin itself, and it is hydrophilic as hell, so its bioavailability might actually be worse.
I read a research paper where esters of GABA with inositol where mentioned as a method of delivering it more efficient into the CNS (I can't find it anymore but these ones also describe it: https://www.researchgate.net/publication/45630223_Selected_Gamma_Aminobutyric_Acid_GABA_Esters_may_Provide_Analgesia_for_Some_Central_Pain_Conditions https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918363/

Compared to benzodiazepines, pregabalin's recreational potential is far lower. Also, one of the problems with gabapentinoids is that their structure-activity-relationship is still not all that well-understood. Gabapentinoids apparently need to be actively transported into the brain via special amino acid carrier proteins. For years, the search for a successor to pregabalin has been slowed down by the fact that compounds that seemed much more potent in the in-vitro binding assays showed little if any increase in in-vivo potency, as their structural modifications would also decrease affinity for the aforementioned amino acid carriers, no longer justifying the significantly more complex synthesis.
I don't think it's recreational potential is really lower, maybe different but at least where I live it's very popular, most people I know who have tried pregabalin in higher doses (300-500mg) rate it much higher than benzos. I only have tried once 150mg+150mg a few hours later and it was really strong, when I stood up I always stumbled around and the muscle relaxation was really heavy, a bit like alcohol just without the mind feeling of it, much more clear and bright with a heavy euphoria, I was in a social setting with friends and although I also find some benzos euphoric this was way stronger, I guess to get such a strong muscle relaxation you would need so many benzos that it'll cause blackouts.

But I also guess that it would be hard to make/find really good gabapentinoids as "research chemicals", but that's why I thought that some kind of pro-drug for known ones like pregabalin would make most sense. I believe that there could be some simple analogues/pro-drugs that would be as cheap as for example phenibut, GABOB, picamilon etc. Pregabalin is just GABA with that ethyl-isopropyl unit or like gabapentin with an cyclohexane, GABOB with an OH-unit etc. I also think the chance for severe toxicity of simple amino acid analogues is a bit lower than for example all those cannabinoid and cathinone analogues, or not? I know that some strong poisons have amino acids build into their structure but quite differently than those mentioned structure modifications.


I know about methylmorphenate, I guess that making a para-fluoro or (di)chloro-substitution could increase it's effects? But I plan to get a small sample just for the collection as I really like it's structure and morpholines in general. Maybe it's just an imaginary delusion to think morpholine and norbornane stimulants are much smoother and enjoyable but I really liked camfetamine and 3fpm so I'm a bit framed about this.
 
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Soulfake

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some more random chems. PsyMDPV (third below on the right side), gives you a 10m-min psychotic trip and you can't stop using it until the supply runs out ^^ on the left of it a indole-cannabinoid mix with psilocin. Is it possible to replace the indole of psilocin or other indole-based psychedelics with indazole or azaindole as easy as it's being made with the synthetic cannabinoids? If they are so similar that they fit into the target neurons in a similar way when they are replaced in various synthetic cannabinoids why wouldn't it be possible to work similar for psychedelis? The "serotonin stem" doesn't seem to be only based on indoles as for example in Agomelatin it is replaced by naphtalene but still works at the target receptors (would that be possibly for psychedelics, too?)
's
 
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Pomzazed

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So this is the least creative molecule ever, but I'm honestly a tad curious as to whether this one was ever characterized. HDMP actually sounded kind of interesting to me.

As an old man with a job, short-acting comfortable-but-not-euphoric stimulants sound perfect lmao
Doesnt work like MDMA, still works as pure stimulant and abit stronger than MPH itself,
methylphenidate doesnt take phenetylamine?s SAR,
It overlays well with cocaine, so use cocaine?s SAR to design on that!
 

Hodor

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Regarding the molecule on the top left, it's probably not going to be particularly potent. Shulgin made thio-substituted analogues of DOM, and noted that replacing even a single methoxy with a methylthio group decreased their potency by a factor of ~10 if the substitution was at the 5-position ("5-TOM"), and by a factor of ~15 if it was at the 2-position ("2-TOM"). Unsurprisingly, replacing *both* oxygens with sulfur resulted in a compound ("bis-TOM") that produced what might at best have been threshold effects at a dose as high as 160 mg. Compare this to the parent compound, DOM, already producing strong psychedelic effects at 5 mg.

Thus, bis-thio-Bromo-DragonFLY would probably require a relatively high dose to be psychoactive, which would likely fail to justify the complex synthesis from a financial standpoint.
 

Soulfake

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So this is the least creative molecule ever, but I'm honestly a tad curious as to whether this one was ever characterized. HDMP actually sounded kind of interesting to me.

As an old man with a job, short-acting comfortable-but-not-euphoric stimulants sound perfect lmao

I think I have seen this one somewhere in an phenidate-analogues research paper where the different affinities where listed but I can't find it anymore. But it would be nice to see more analogues without halogens, I know they are not "bad" themself or something like this but somehow I like compounds that look more "natural". I guess it should be certainly active similar to the 3,4-dichloro version but I can't remember the potency and affinities from the paper. It would be really great if there would be a complete website with all the informations about affinities, potency and other structural differences etc. and going a bit more in depth than usual drug-wikis.
 

aspiringdrugdesign

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Interesting Read:


https://en.wikipedia.org/wiki/Amfonelic_acid

"In studies it proved to be a potent and highly selective dopamine reuptake inhibitor (DRI) in rat brain preparations.[4][5] A study found a moderately long half-life of approximately 12 hours and a dopaminergic potency approximately 50 fold that of methylphenidate in rat brain preparations.[6] Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in 5HT and 5HIAA.[7] Amfonelic acid displays no activity in the norepinephrine system.[8]Despite its different mechanism of action, amfonelic acid displays discriminatory substitution with 150% the stimulant potency of dextroamphetamine.[9] Amfonelic acid has been shown to be neuroprotective against methamphetaminedamage to dopamine neurons.[10] It also increases the effects of the antipsychotic drugs haloperidol, trifluoperazine and spiperone.[11] Rats are shown to self-administer amfonelic acid in a dose-dependent manner.[12]
Though AFA was discovered in the course of antibiotic research, there is very little data available on the drug's antimicrobial activity. In 1988 the biologist G.C. Crumplin wrote, "[AFA] is less active against bacteria than are many other 4-quinolones, but studies in our laboratory on selected mammalian cell lines have shown it to be markedly more toxic to these cells than are the 4-quinolones that are more active antibacterial agents. Furthermore, it can be shown that sublethal doses induced marked changes in the pattern of proteins produced by the cell, thus suggesting a possible effect of 4-quinolones on gene transcription in mammalian cells."[13] When evaluated via broth microdilution the MIC of AFA for Escherichia coli is 125 μg/mL, a concentration thirty times higher than the MIC for nalidixic acid in the same E. coli strain.[1]"

Seeing a lot of similarities led me to these ideas:








Would love insight or some studies to read about either nalidixic acid or amfonelic acid
 

Hodor

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More toxic than the fluoroquinolones? Ugh.

Fluoroquinoloes are extremely effective at killing bacteria, but nowadays they are no longer a preferred first-line-treatment unless the infection is *really* serious (ex.: pneumonia), due to the chance of suffering rare, but potentially crippling side-effects involving damage to tendons, muscles, cartilage and bones.
 

Soulfake

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Wasn't amfonelic acid available as a "research chemical" once or am I confusing it with something similar?
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some random chems


---------------------------------------------------------------------------------------------------edit 20.02


edit: more chems, camfetamine is said to have opioid properties although I still couldn't find that damn paper that explains it's mechanism besides dopamine-induced pain resistance but you can see the similarity to drugs like tilidine, tramadol or pethidine so I drew some molecules with those ester and 3-hydroxy substitutions you can find on many analogues of the named opioids (as well as some nonsense diphenyl-substitutions and cocaine-like stuff along my usual camfetamine/norbornane analogues) The last ones are hypothetical pro-drugs to some phenmetrazine-derivates similar to bupropion's metabolites (if you change the fluoride from the first one with chlorine you get bupropion) although they probably won't be really recreational.
 
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sekio

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"Acetylmethadone"


"Butyrylmethadone"


"Ethadone"


Thiophene analog of methadone. Reminds me of the thiambutenes

Also consider e.g. isomethadone and dipipanone modified as per above... and also, changing the ketone to an alcohol or ester a la LAAM / methadol.


Or even reversed ester... a bit of a kludge but maybe.


there's also the ketone -> sulfone analogs which are known... IC-26


So maybe also...

There's probably a SAR paper on these out there... clubcard? :)
 
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MmmLysergamides

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"DimethyltryBtamine"
If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.
 

Pomzazed

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It seems to autoignite on air exposure like many alkylboranes...

Also, that BR3 is a strong lewis acid, and wont work in the same way as N in tryptamine
 

Hodor

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If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.
Boron is less electronegative than even hydrogen. You do not need a catalyst for it to undergo rapid oxidation. In fact, organoboranes tend to spontaneously ignite upon exposure to air, even at temperatures below 0 degrees Celsius.

Boron also lacks a lone pair of electrons, which is likely to render the compound non-psychoactive (unless you consider neuropathic damage to be a form of psychoactivity).
 

S.J.P.

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"DimethyltryBtamine"
If its even active I wonder how potent it would be because MAO most likely wouldn't be able to metabolize it easily.
Replacing the boron with a phosphorous would make this more analogous to the parent compound, but even those are highly unstable to oxidation.
 
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