4-MAR stereoisomers SAR

[paracelsius]

I wouldn’t call IC50 of 0.5mM “active”:

Aminorex IC50(MAO) = 5X10^(-4)M (in rat liver microsomes). 5X10^(-4)M= 0.5mM = 500,000nM correct me if I am wrong.

"MAO-inhibitory properties of anorectic drugs" J. Pharm. Pharmac., 1973, 25, 576.

Don’t know about 4-MAR, 4,4-MAR and others analogs. I confused with another paper. I don’t think it’s been done for 4-MAR and other analogs. Only parent Aminorex that I can find.

For monoamines activity:
Aminorex EC50 (DA, NE, SERT) release ~ 10nM, 15nM, 200-400nM resp:

Aminorex analogs. ACS Chem Neurosci. 2018 October 17; 9(10): 2484–2502. doi:10.1021/acschemneuro.8b00415

Now, the IC50 for MAO inhibition is 50,000, 30,000 and 1,200-2,500 times higher than the EC50 for DA, NE, SERT release resp. So I don’t think MAO inhibition is significant at psychoactive doses of Aminorex. True, humans are not rats, tho I met some that are worse!

So using ARs as MAOIs with DMT won't work imo: you'd be loooooong dead of massive monamines release and seizures before reaching dose that significantly block MAOs. Very very dead! The difference IC50 psychoactive dose v MAOI dose is just to high!

With all due to respect to Pr Nichols, imo the Oxazolines are wonderful drugs that suffer bad wrap and stigma and mystic at same time. No worse than the most popular drug in the part of world I live in: methamphetamine! or any other stim for that matter. I think Pr Nichols got shaken after some stupid kids ODed on his 4-MTA compound and died! Understandbly, he is overcautious.

As for pulmonary hypertension (due to SERT release) seen with AR in Germany and Swiss, keep in mind this was in ppl taking the drug for weight loss (10mg tid) for six months straight! twice a day for six month! Steady state drug conc. in plasma/brain nonstop for 6-months considering the compound long T1/2 duration already!!!!!

I mean, they didnt know at that time that Aminorex is actually a potent triple releaser (unlike plain amph), more like MDMA but at least 10x more potent!!! A bit like meth with increased SERT release (SERT release of meth is ~700nM and AR is ~200-400nM, DA and NE release are similar range meth and AR). So AR is somewhere in between meth and mdma. Actually Oxazolines are really rather unique drugs, a class of themselves.

Now, you wouldn’t want be taken 100 mg MDMA twice a day for six month straight do you?

Yeah actually unlike Meth and MDMA, Aminorex IS NOT NEUROTOXIC, either to DA or SERT neurons:

"The Effects of Aminorex and Related Compounds on Brain Monoamines and Metabolites in CBA Mice" J. Pharm. Pharmacol. 1997, 49:89-96 - doi​

Have to reread that paper. Pretty thorough study of possible neurotoxicity of AR, 4-MAR and all its stereoisomers (cis/trans, +/-) compared to MDMA and Fenfluramine in mice.

It doesn’t deplete DA/SERT either, unlike meth/mdma (same paper). Which is why you don't have that suicidal depression and/or anxiety on “suicide mondays” on comedown from the two other drugs! Strangely, Oxazolines after-effect is the opposite, antidepressant! (can't figure the mechanism of that one tho!)

Now, I am not saying Aminorex (or other ARs) have no issues. SERT hyperthermia/dehydration may still fry your brain!

“The poison is in the dose, not the drug” as my avatar, Paracelsius, credited as father of modern Pharmacy, once said.

In any case, I’d treat Aminorex, 4-MAR and all Oxazolines stimulants like I would MDMA: take a BREAK...take a Break...take a Break...take a Break

edit: can't find data re: cardiotoxicty due to 5HT2b agonism of oxazolines. Pretty sure Pr Nichols knows that. which is an issue in chronic use for sure.

 

[paracelsius]

Lately, I’ve seen lots of talk and interests here on BL and some other forums about the oxazolines stims. Would be nice to update all the threads on these compounds on BL or maybe get a 4-MAR HR thread with as much info as possible in one place. So some stupid kid reading online and cooking 4-MAR in his kitchen wont end up dead!. I’ll see whenever I have time to collect all the data and if the interests warrant.... yo’all have a good’day!

 

[Fertile]

The thing is - considering how rare 4MAR is, their are quite a few unexplained deaths recorded. Nobody knows why, But I asked Dr. Dave the direct question and the answer was 'aminorex isn't an MAOI, 4MAR is'. And I suppose it all boils down to if you trust Dr. Dave. Given that he's the most respected researcher into psychoactive and entactogen drugs alive.

I'm someone who is prepared to trust him and given that from scratch, aminorex is MUCH simpler to make, I'm sticking with aminorex. All these people imagining that they HAVE PPA. People who don't consider the steps one has to go through to produce PPA or think it's going to fall of the back of a truck.

Plain aminorex is easier to make, 4MAR has no advantages and seemingly issues. So why moulder on about it.

 

[paracelsius]

My apologies...I thought you quoted Dave Nichols as saying Aminorex is an MAOI. Thats why I mention that ref. So we saying the same thing: Aminorex is not MAOI (at psychoactive doses anyway). I don't know about 4-MAR isomers and analogs. Which is why I said I confused with some other papers dealing the same compounds. For sure Pr Nichols have data on 4-MAR and other 4-sub ARs. Trust him, he certainly knows what he is talking about. Is he still at Purdue, he’s getting old now isn’t he?

Anyhow, yeah you right, I don't know why ppl tend to focus on 4-MAR but plain Aminorex is actually way more better than 4-MAR, more euphoric with no mindfuck and suicidal comedowns. Really better drug. Quite active (at least functional) as low as 5mg!

I guess thats is b/c of legal issues since AR is in UN ban list but not 4-MAR iirc. Yeah sure, synth pretty straighforward from ppa (dog med),easier than meth shake’nbake if you know what you doing. Plus easy access to the dextro and levo from chiral ppa.... but you can’t discuss synth here.... yo’all have a good’day

 

[Fertile]

No -4MAR. I admit I don't know why but I know other classes in which increasing alkyl length produces MAOI activity so it isn't as if it's a one-off.

But AR just needs a (substituted benzeladehyde). Nitro-alcohol, aminoalcohol, product. PPA boasts stereocenters so you have to deal with that. OK L-PAC is the best option BUT nobody has demonstrated ring-substituted L-PAC. Plus reductive amination with ammonia or using formamide (both giving mixture of isomers doesn't sound good. For decent yield one would need to resolve isomers and oxidise back to achiral compound,

So practically, 4MAR only works if you have PPA and then only for unsubstituted product.

 

[unodelacosa]

People who don't consider the steps one has to go through to produce PPA or think it's going to fall of the back of a truck.

There is a source in the wild, so to speak. It's against site rules to source, so let's just say there are some interesting vet meds for treating urinary incontinence in certain mammals. @paracelsius knows what I mean.
This would be neither viable nor adequate for scaled-up production, but to the kitchen chemistry dilettante this could be useful.

I guess it's also possible to extract cathine from catha edulis, provided one has a source. Though in many countries, Khat is already illegal, and it's still not very practical.

As far as PPA synths goes, as noted, we can't discuss it here, but it's not impossible.
Relevant links:

• https://www.erowid.org/archive/rhodium/chemistry/ppa.html
• https://www.erowid.org/archive/rhodium/chemistry/ppa.synthesis.html

And I suppose it all boils down to if you trust Dr. Dave.

Well… if you think about it… it boils down to if you trust @Fertile, doesn't it?
I do believe you, FWIW. It's just that rather than dissuade me from my interest in 4-MAR,
I'm now also very curious about aminorex.

Plain aminorex is easier to make, 4MAR has no advantages and seemingly issues. So why moulder on about it.

See – that's where I disagree. If one has PPA, I think 4-MAR is easy to get to via KOCN.
Hence: the noted mouldery.

I find it interesting both of you – @Fertile and @paracelsius – consider aminorex to be the superior drug to 4-methylaminorex.
That's certainly something to ponder, and I thank you both for the proverbial food for thought

 

[Fertile]

Well... hah, ha.h.... good luck with THAT,

 

[fastandbulbous]

I've searched for this but found nothing about 4-MAR being an MAOI. I concede it certainly seems to be cardiotoxic.


@paracelsius – can you weigh in on this for us, please? In this post you state that aminorex and 4-methylaminorex are both not MAOIs. And I could've sworn I read somewhere that 4-methylaminorex turned out not to be significantly neurotoxic. It just has a really long duration of effects and likely a long half life to elimination, plus a sketchy cardiotoxicity profile.


Ok then, fair enough.

I'd like to see data on the degree these compounds inhibit monoamine oxidase and what the relative viability of the compound might be for the inclusion w/some orally ingested DMT to form a 4-MAR-huasca experience…

The fact that an alpha alkyl group is on a target for MAO, pretty much ensures it will be a competetive inhibitor. How much an inhibitor is down to god knows how many factors, but an alpha methylgroup prevents the enzyme from becoming the active conformation (as does sticking groups with lone pair electrons on the mainly para, but occasionally meta position ofthe ring). The evolution of our whole metabolic system never really was designed to cope with alpha methyl phenethylamines (a few plant alkaloids excepted), or replacing the phenolic groups of catecholamines with other groups (especially thiomethyl, which uses sulphur to mimic oxygen, but with totally different results).
That aminorex works at all, is pretty amazing, seeing the GI tract is full of MAO isoforms, hell bent on deactivating bacterial decarboxylation of amino acids.

 

[unodelacosa]

The evolution of our whole metabolic system never really was designed to cope with alpha methyl phenethylamines

Interesting theory. And yet our metabolic systems do, in fact, cope with said alpha-methylations… eventually anyway, lol.
I'm thinking about this and going from, say, 2C-B to DOB enhances both potency and duration.
Moreover, MDMA neurotoxicity is brought on by alpha-methyl-dopamine, and of course dopamine and adrenaline are PEAs while serotonin is a tryptamine.

I suppose you're right if we're using metabolic duration and half-life to elimination as parameters with which to judge.
But if psychological growth, personal insight, and enjoyment of life are significant to you, then I argue our metabolic systems are perfect for both coping and thriving, with the right psychotropic tools.

Well... hah, ha.h.... good luck with THAT,

Thank you, brother. I'm not sure which part you're wishing me good luck with, but I don't mind the extra suerte regardless

And it's all gravy biscuits, my guy. Happy Thanksgiving and much love and respect.

 

[fastandbulbous]

Interesting theory. And yet our metabolic systems do, in fact, cope with said alpha-methylations… eventually anyway, lol.
I'm thinking about this and going from, say, 2C-B to DOB enhances both potency and duration.
Moreover, MDMA neurotoxicity is brought on by alpha-methyl-dopamine, and of course dopamine and adrenaline are PEAs while serotonin is a tryptamine.

I suppose you're right if we're using metabolic duration and half-life to elimination as parameters with which to judge.
But if psychological growth, personal insight, and enjoyment of life are significant to you, then I argue our metabolic systems are perfect for both coping and thriving, with the right psychotropic tools.


Thank you, brother. I'm not sure which part you're wishing me good luck with, but I don't mind the extra suerte regardless

And it's all gravy biscuits, my guy. Happy Thanksgiving and much love and respect.

We are adaptive creatures, both metabolically and psychologically. Just need to know which routes end in a black hole and which end in another step to enlightenment (so far, I've avoided the black hole endings and hope long may it be. I just hope to pass on to others, there are areas which on 'ye olde maps' style, there are real 'here be monsters' pitfalls!

 

[unodelacosa]

We are adaptive creatures, both metabolically and psychologically. Just need to know which routes end in a black hole and which end in another step to enlightenment (so far, I've avoided the black hole endings and hope long may it be. I just hope to pass on to others, there are areas which on 'ye olde maps' style, there are real 'here be monsters' pitfalls!

It's interesting to think perhaps this "olde map" functions as a metaphorical cartograph of our own "inner space." If this is so, then maybe pitfalls marked "here be monsters" are the monsters inside of us, so to speak, our proverbial "inner demons."

Either way, it's a powerful metaphor; I like it.

 

[Delmonte421]

I replied to the IMAGE you supplied. Adding a 2,5-dimethoxy and ESPECIALLY a p=Br just meant the body will be deprived on it's main metabolic pathway. People have made p-F 4MAR and the duration is just toooooo long.

So we tried the p-Methyl AR first - because that provides a sacrificial moiety so duration goes down. It also significantly made the compound almost totally SERT selective. Then we made the m-methyl and that was DAT>NET>>SERT. So a 2:1 mixture of the two was an excellent MDMA substitute, but not elegant. Thus having proven the biosteric minimum WOULD fit an MD moiety, we made the 34-MD derivative of aminorex. NOT 4 methylaminorex. Because I am reliably informed (Dr. Dave) that it's an MAOI and so we stayed WELL clear.

If you know 4MAR is a significant MAOI, you would respect the fact that if it's also modulating monoamine release - it's an accident waiting to happen.

PLAIN aminorex is the better scaffold. But it has 5HT2b affinity (as does 4MAR) - so while fine on an occasional basis, long-term use is likely to lead to COPD. Both AR 4MAR have caused COPD in thousands of people. so it's only safe if it's going to be used occasionally. Straight stimulants lead to binges, entactogents rarely.

Read the story of the Florida lab busted for making 4MAR. They had all been using daily for months, they all had COPD, specifically heart valve damage.

So I repeat - people have looked into this scaffold, it's a possible MDMA replacement but as I have already stated - too complex synthetically.

But by all means, provide a facile synthesis and we will continue.

Wow im actually very impressed with your Med chem knowledge!!!! Who is Dr.Dave as I would like to learn more about what you guys are talking about. Unfortunately I didn't take med-chem classes in grad school just some advanced orgo classes and advanced orgo analytical work like how NMR works etc. Steriospecfic reactions are very difficult as you probably know more then I do and with the use of new drugs like Dr.Shulgun did makes me nervous for you guys as simply changing a little thing can kill you as you once agin orobbanly know more then I do. Hope you guys stay safe in your clandestine adventures.

For reference before I went to grad school I was worked in pre-clinical formulations for Pfizer and did work on small molecules and large Bio-molecules. I know on the research side they saw a lot of animal deaths from shit they we're synthesis and trying, non-illicit, for very simple changes. We all know the story with viagra and how it was for blood pressure until the phase one clinical trial males started reporting getting boners lol I worked on the development side so by the time we got it they already had the med chemist doing the 25 step reactions and the chem dev guys trying to make the synthesis more cost efficient. Any who, we made the formulations for all the animals depending on the study and gave the formulated API to the vet techs for administration to the animals and would hear about all the toxicology reports and how just moving a methyl group can literally increase the activity of certain compounds but once again this isn't my background as I don't know as many reactions as you do @Fertile

Also for reference to our convo before, I actually have a DEA license #, or my company/university does for ordering certain things we may be working on so thats why I personally don't risk it as I would lose a shit ton if I started making shit on my own. Sucks cause I have access to ALOT of reagents and precursors one may not be able to get their hands on.

 

[Fertile]

Dr. David Nichols - the worlds most well qualified man when it comes to 5HT2b ligands. He has published hundreds of papers.

Don't know instrumentation specialists - they are an important resource. We had 1 guy who JUST did GC-MS & NMR all day. Not my cup of tea, but buy did I get to see BAD synthesis - the synthetic CB1 ligands being the worst with dimers, trimers and polymers common. MW too high for them to vape so they pyrolize. Expect a cancer spike.

I couldn't bring myself to sacrifice animals and I'm disabled. So I got to design. Nothing radical - always additive from what is known.

Uni is GREAT. I nicked an entire distillation set, Buchner and even an Ohaus dial-a-gram that was in storage.

Chemicals - well just open a company with your uni as the address - put it through their own payment scheme and just add the cash for what YOU ordered.

I know people who made EVERYTHING at uni. As long as you pay for what you use, they don't mind. After all, post-grad, it's up to YOU so who is gonna check if you hand over cash and ask them to pay bill?

Faint heart and whatnot.

 

[Delmonte421]

Dr. David Nichols - the worlds most well qualified man when it comes to 5HT2b ligands. He has published hundreds of papers.

Don't know instrumentation specialists - they are an important resource. We had 1 guy who JUST did GC-MS & NMR all day. Not my cup of tea, but buy did I get to see BAD synthesis - the synthetic CB1 ligands being the worst with dimers, trimers and polymers common. MW too high for them to vape so they pyrolize. Expect a cancer spike.

I couldn't bring myself to sacrifice animals and I'm disabled. So I got to design. Nothing radical - always additive from what is known.

Uni is GREAT. I nicked an entire distillation set, Buchner and even an Ohaus dial-a-gram that was in storage.

Chemicals - well just open a company with your uni as the address - put it through their own payment scheme and just add the cash for what YOU ordered.

I know people who made EVERYTHING at uni. As long as you pay for what you use, they don't mind. After all, post-grad, it's up to YOU so who is gonna check if you hand over cash and ask them to pay bill?

Faint heart and whatnot.

I'm honestly too much of a pussy man. When I was in grad school I would think about it but now I got a wife and kids that need me. Also the ordering process goes through mutable approvals etc I'd get caught haha

With your disability are you still able to work in a lab or do you moistly do theoretical chemistry work? I saw a job for a theoretical chemist that would work remotely, I'm assuming they would come up with the synthesis scheme and have other chemist actually preform it in the lab.

I do a lot of HPLC, GC and TLC work which I hate. I am an orgo guy at heart but I do what I gotta to pay the bills

 

[Fertile]

I do freelance work - I FIND actives that are not controlled. Never had a police visit but I know that your NSA in conjunction with GCHQ gave me a hard time. They killed my PC and any device within Bluetooth range....

But they destroyed evidence already coped to a DVD.... so they screwed up.
I even got a tail - full team of 8. I took my 35mm twin reflex camera out with me and 'shot' them all. They gave up - it's my own handwriting. Don't run, make your 'cost' too high for them.

I will give you someone else's handwriting. He kept owls - BIG owls. 14 cages of them. Then he buried stuff in the enclosures so the cops KNEW it would be expensive to check.... so his 'cost' was too high.

 

[Delmonte421]

I do freelance work - I FIND actives that are not controlled. Never had a police visit but I know that your NSA in conjunction with GCHQ gave me a hard time. They killed my PC and any device within Bluetooth range....

But they destroyed evidence already coped to a DVD.... so they screwed up.
I even got a tail - full team of 8. I took my 35mm twin reflex camera out with me and 'shot' them all. They gave up - it's my own handwriting. Don't run, make your 'cost' too high for them.

I will give you someone else's handwriting. He kept owls - BIG owls. 14 cages of them. Then he buried stuff in the enclosures so the cops KNEW it would be expensive to check.... so his 'cost' was too high.

As someone who loves chemistry as much as you obviously do, please be careful. I don't want someone like you to disappear from these forums. I like looking up your comments and learning what tech and synthesis your talking about.

Thats crazy that they look into your legal synthesis so much but I guess if you can produce legal analogs then you most defiantly can make the real thing. Whats your take on all the new opioid RC's coming out now, any favorite that you personally like? also for oxycodone synthesis, it really is that expensive to produce and you have to use poppy plants because the synthetic route would be too expensive or impossible?

I unfortunately took some fake M30's for awhile and got physically addicted and just switched to oxy and plan on going onto subs when I can't afford the oxy anymore lol gotta feed the kids nd wife and not my inner addict haha But I have no fucking idea what was in them as they didn't test for fent, and it should be known that my only ROA is oral no sniffing or IV.

 

[Fertile]

Last opioid that went commercial was U-47700 although brorphine can be modified in several ways. The GOOD opioid is in my head - not on paper. Took a hell of a lot of work to find a 3 step synthesis. All legal.

 

[Fertile]

BTW how did everyonemiss example 13 of the George Ireland Poos patent?

It clearly shows 3,4-MD aminorex to be active.

I'm BETTING that the benzene could be swapped for a 1-benzofuran to make the 5/6 APB homologues.

It doesn't seem to have 5HT2a affinity so no point in any of that 2,5-dimethoxy-4-<something> nonsense but the MD ring shows that their IS space to introduce SERT activity. The MD may be preferred since it can be metabolised.

The p-Me aminorex is SERT selective, m-Me aminorex DAT/NET selective so a 2:1 mixture does an excellent job as an MDMA mimic. It might be cheaper as well.

 

[unodelacosa]

It doesn't seem to have 5HT2a affinity so no point in any of that 2,5-dimethoxy-4-<something> nonsense

Whoa, are you sure? 2C-B-Aminorex is a psychedelic compound.

The p-Me aminorex is SERT selective, m-Me aminorex DAT/NET selective so a 2:1 mixture does an excellent job as an MDMA mimic. It might be cheaper as well.

I've seen you opine this before. It's definitely something I would like to try. Have you tasted this yourself, or at least know anyone personally who's done it?

 

[unodelacosa]

I unfortunately took some fake M30's for awhile and got physically addicted and just switched to oxy and plan on going onto subs when I can't afford the oxy anymore lol gotta feed the kids nd wife and not my inner addict haha But I have no fucking idea what was in them

Hang on, man. Earlier you said:

I'm honestly too much of a pussy man. When I was in grad school I would think about it but now I got a wife and kids that need me. Also the ordering process goes through mutable approvals etc

So you'll roll the dice on some sketchy-ass "Dirty 30s" like a mofo, but when it comes to sneaking out a few chems you're all of a sudden citing your responsibilities as a family man? … Live a little – nothing ventured; nothing gained. Just be confidant and smooth and have excuses already in mind, on deck, ready to go.

I'd get caught haha

Yeah especially with that attitude, right?

I'm just playing Devil's Advocate over here and (mostly) just messing with you. But at the same time, this kind of language only serves to prepare your nervous system to fail. Believe in yourself, whether its pinching university chems, changing career paths to seek better opportunities, or kicking off a new startup venture, envision your own success. Document the steps your take; mirror the behavior and patterns of those who have a similar success to what you seek, and speak kindly to yourself and about yourself.