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N&PD Moderators: Skorpio | thegreenhand
I Like to Draw Pictures of Random Molecules
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Dresden
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aced126,
I'm not entirely sure either, as N,N-dimethylamphetamine is only 1/10th the potency of methamphetamine.
As for your latest molecules, the benzylic, substituted with an an oxygen amphetamine molecule will not form. The N and O are one carbon apart again. Not sure if using a piperidine ring with the nitrogen spaced only one carbon from an oxygen would work or not. I kind of think it would for some reason.
As for the phenyl-cyclobutyl-amine, it to me looks like transcyclopropylamine (its cyclopropyl homologue), which is an MAOI.
Finally, the carbonic anhydride MDxx thing won't work, as upon contact with water such as in saliva for example, the 3-Ar-O-(C=O)-O-4-Ar ring system will break apart.
I'm not entirely sure either, as N,N-dimethylamphetamine is only 1/10th the potency of methamphetamine.
As for your latest molecules, the benzylic, substituted with an an oxygen amphetamine molecule will not form. The N and O are one carbon apart again. Not sure if using a piperidine ring with the nitrogen spaced only one carbon from an oxygen would work or not. I kind of think it would for some reason.
As for the phenyl-cyclobutyl-amine, it to me looks like transcyclopropylamine (its cyclopropyl homologue), which is an MAOI.
Finally, the carbonic anhydride MDxx thing won't work, as upon contact with water such as in saliva for example, the 3-Ar-O-(C=O)-O-4-Ar ring system will break apart.
I don't think they're prodrugs. Thinking of N-pyrros like MDPV and a-PHP.
Prolintane which is without the beta-keto is active too though... Maybe it's a whole different SAR for these compounds with long alkyl chains on the alpha carbon. They might cause monoamine release differently than amph and cathinones too... I think they're regarded as reuptake inhibitors instead of releasers. If they're recreational surely enough they don't just block the transporters tho, I don't know if anyone looked closely enough to know though
sekio
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MDPV is known to be a reuptake inhibitor with no monoamine releasing effects, and stuff like mephedrone are mixed releasers/reuptake inhibitors.
I think SAR of DA releasers requires a moderately basic amine residue for best efficacy, that means secondary amines are better than primary amines, and tertiary amines are at the bottom. Look up the effective dosage of something like benzphetamine compared to methamphetamine.
Conversely MDPV can get away with bulky substituents on the amine that serve to increase lipophilicity & metabolic stability at the expense of efficacy as a releasing agent. But Isuspect that by the time you get to something like alpha-propyl-phenethylamine there is going to be minimal releasing efficacy.
I think SAR of DA releasers requires a moderately basic amine residue for best efficacy, that means secondary amines are better than primary amines, and tertiary amines are at the bottom. Look up the effective dosage of something like benzphetamine compared to methamphetamine.
Conversely MDPV can get away with bulky substituents on the amine that serve to increase lipophilicity & metabolic stability at the expense of efficacy as a releasing agent. But Isuspect that by the time you get to something like alpha-propyl-phenethylamine there is going to be minimal releasing efficacy.
S - always direct and to the point.
Prolintane is VERY mild indeed - you would be hard-pressed to get a buzz.
As for bulky substitution on the beta (trivial name) like a phenyl group (the first aromatic being a p-toluene), gives something that, is identical to pyrovalerone. The MW is higher, but so is the LogP and so, in an elegant twist, it's the same potency as pyrovalerone. Lefetamine was marketed as a stimulant, the minor NMDA and partial opiate agonist affects were discovered later. I read of it being trialled in Italy (I think) in a comparison with methadone and buprenorphine and although it helped, it wasn't seen as useful. I believe a cyclohexyl moiety will replace the benzene-ring. I have the papers on tests concerning both isomers and the (S) isomer actually has more NMDA activity but at the doses needed for analgesia, seizures occur (showing the AMPA affinity). That's why the 2-substituted were a bad idea (IMO). It interested me because it's one of the few opioids that break the rules and have the basic nitrogen in the benzyl position (like BDPC & ciramadol). Lednicer actually started with a p-toluene and 4-cyclohexanone, not the stupid, murderous super-potent agonists, this is a very useful insight into these rule-breakers. I need some software that takes a group of training compounds and finds the 3D coincidence of given moieties of said training set. Any suggestions gratefully recieved.
I know I keep banging on about it, but Marvinsketch online is free and gives LogP & PKa. The best example I can think of is EXP-561. It's about 98% protonated in the blood so at any one time, only 2% of the amount in the blood-stream can pass into the brain so SLLLOOOWWWW onset. Just using Marvinsketch and remembering Lipinski's rules of 5 mean that people can design stuff that would reach the brain.
Oh yes, I've just remembered. Seiko, the 5-carbon amphetamines do exist. They work in a different manner. It IS a (mild) stimulant but it's effects are upstream of the monoamine releasers and so it's an insight into the next level of the cascade. I can find the patent number if you can't.
I'm afraid that my education is from an era where none of these cascades were understood.
Can someone recommend a windows or UNIX app that allows a training-set of compounds be used to find shared moities in 3D. I saw one for opioids BUT it doesn't cover the alkene on allylprodine/14-Cinnamoyloxycodeinone (for example). Another is the benzylic-nitrogen opioids BDPC, ciramadol (and Lednicer's earlier, pethidine strength opioids which just had a cycloexanone. It's like the N & O can be swapped.
Prolintane is VERY mild indeed - you would be hard-pressed to get a buzz.
As for bulky substitution on the beta (trivial name) like a phenyl group (the first aromatic being a p-toluene), gives something that, is identical to pyrovalerone. The MW is higher, but so is the LogP and so, in an elegant twist, it's the same potency as pyrovalerone. Lefetamine was marketed as a stimulant, the minor NMDA and partial opiate agonist affects were discovered later. I read of it being trialled in Italy (I think) in a comparison with methadone and buprenorphine and although it helped, it wasn't seen as useful. I believe a cyclohexyl moiety will replace the benzene-ring. I have the papers on tests concerning both isomers and the (S) isomer actually has more NMDA activity but at the doses needed for analgesia, seizures occur (showing the AMPA affinity). That's why the 2-substituted were a bad idea (IMO). It interested me because it's one of the few opioids that break the rules and have the basic nitrogen in the benzyl position (like BDPC & ciramadol). Lednicer actually started with a p-toluene and 4-cyclohexanone, not the stupid, murderous super-potent agonists, this is a very useful insight into these rule-breakers. I need some software that takes a group of training compounds and finds the 3D coincidence of given moieties of said training set. Any suggestions gratefully recieved.
I know I keep banging on about it, but Marvinsketch online is free and gives LogP & PKa. The best example I can think of is EXP-561. It's about 98% protonated in the blood so at any one time, only 2% of the amount in the blood-stream can pass into the brain so SLLLOOOWWWW onset. Just using Marvinsketch and remembering Lipinski's rules of 5 mean that people can design stuff that would reach the brain.
Oh yes, I've just remembered. Seiko, the 5-carbon amphetamines do exist. They work in a different manner. It IS a (mild) stimulant but it's effects are upstream of the monoamine releasers and so it's an insight into the next level of the cascade. I can find the patent number if you can't.
I'm afraid that my education is from an era where none of these cascades were understood.
Can someone recommend a windows or UNIX app that allows a training-set of compounds be used to find shared moities in 3D. I saw one for opioids BUT it doesn't cover the alkene on allylprodine/14-Cinnamoyloxycodeinone (for example). Another is the benzylic-nitrogen opioids BDPC, ciramadol (and Lednicer's earlier, pethidine strength opioids which just had a cycloexanone. It's like the N & O can be swapped.
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aced126
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Well in lefetamine you could view the nitrogen as the 1 carbon away from the phenyl, but what probably happens in the binding site is the phenyl ring 2 carbons away conforms to the positive residues rather than the alpha substituted phenyl. I think the alpha phenyl is analogous to the cyclohexene ring in morphine. Thus if it were hydrogenated potency might increase as you said. I posted a few compounds based on these ideas a couple pages back
Nagelfar
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Methylphenmetrazidate?
Napthyl variant? Rather bulky looking.
And if you fuse the carbmethoxy:
Interesting, but probably isn't a ligand at all, haha.
Nagelfar
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Inspired by the nitrogen on the 3β-Carbamoyl cocaine analogues being roughly where it would be on the fentanyl positioning of its similar backbone to methylphenidate with which cocaine overlays. The position of the carbmethoxy similarly inspired by MPH using that very same nitrogen group as a convenient way to host it. The phenylethyl on the tropane lines up with where fentanyl's is on its piperidine using the MPH orientation too. I actually quite like this one for those reasons.
Adolf - sorry for slow response. I'm afraid synthesis discussion is not allowed. I think I can tell you that the 3 reagents you need are all in Aldrich - you have to destabilize Hs on the carbon you want to add to... I think that's enough for you to figure out while I'm not naming any chemicals, conditions or solvents.
I advise everyone to read Derek Lowe's pages in Science Translatable Medicine. 'Things I won't Work With' shows serious chemistry can be seriously funny as well http://blogs.sciencemag.org/pipeline/archives/category/things-i-wont-work-with FYI I've worked with 2 things in his list. I remember him writing that during the end of the 19th century, you could find out who was working with nitroso compounds by turning to the obituaries. It STILL happens. A couple of years ago, a girl was in the uni lab, unattended, while working with t-butyl lithium. Now, if your going to work with this crazy stuff - expect flames. She managed to drop the syringe & cover her body. No lab-coat, a synthetic top that turned into boiling plastic; all in all, not good. What is worse is that an emergency shower was 10 feet away. WHATEVER you are working with, work out the risks & have a plan. That she was inexperienced & not even wearing a lab-coat spelt her end.
If you wonder WHAT crazy stuff I worked with, diethyl cadnium (OK, he said dimethyl but let's not split hairs) and Magic methyl. The latter had been used for years but after a Dutch researcher killed himself with a small spill, it was dropped. You notice this over time. You don't see periodic acid much - I seem to remember the Japanese researchers who looked at mitragynine made the 7-hydroxy using it....
Basically, a lab is a dangerous place to be and during ones education, you soon found out who the passion fingers was (fucks everything they touch) in the form of a girl who was refluxing diethyl ether in a 3-neck flask.... without the stopper being in the unused neck. Ether flames are amazing! But not from close up :-(
I advise everyone to read Derek Lowe's pages in Science Translatable Medicine. 'Things I won't Work With' shows serious chemistry can be seriously funny as well http://blogs.sciencemag.org/pipeline/archives/category/things-i-wont-work-with FYI I've worked with 2 things in his list. I remember him writing that during the end of the 19th century, you could find out who was working with nitroso compounds by turning to the obituaries. It STILL happens. A couple of years ago, a girl was in the uni lab, unattended, while working with t-butyl lithium. Now, if your going to work with this crazy stuff - expect flames. She managed to drop the syringe & cover her body. No lab-coat, a synthetic top that turned into boiling plastic; all in all, not good. What is worse is that an emergency shower was 10 feet away. WHATEVER you are working with, work out the risks & have a plan. That she was inexperienced & not even wearing a lab-coat spelt her end.
If you wonder WHAT crazy stuff I worked with, diethyl cadnium (OK, he said dimethyl but let's not split hairs) and Magic methyl. The latter had been used for years but after a Dutch researcher killed himself with a small spill, it was dropped. You notice this over time. You don't see periodic acid much - I seem to remember the Japanese researchers who looked at mitragynine made the 7-hydroxy using it....
Basically, a lab is a dangerous place to be and during ones education, you soon found out who the passion fingers was (fucks everything they touch) in the form of a girl who was refluxing diethyl ether in a 3-neck flask.... without the stopper being in the unused neck. Ether flames are amazing! But not from close up :-(
Why not find the overlay between RTI-55, amfonelic (and oxolinic acid) & Benocyclidine. I should add that experimentation shows that the most electron-withdrawing groups (where the I is on RT-55_ give the compounds more potent). A good excercise because as you work on it, you will see 3D relationships between moieties, so it gets easier, the longer you work on it.
As a start:
1-tertiary amine.
As a start:
1-tertiary amine.
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Dresden
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The two molecules I drew are mostly planar.
Dresden
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In addition to 5-HT, melatonin, DA, NE, and glutamate etc., I think this would make an awesome addition to our current family of neurotransmitters. No idea how to go about that one, though, unless it is through some kind of extensive natural selection following a designer gene insertion:
3,4,5-trihydroxyphenylethanamine.
This is the stuff of aliens, I believe.
Sound far fetched? Well, sure, but then again, some kind of octopus (and many insects and, to a lesser extent, humans as a TAAR agonist) uses octopamine:
Octopamine.
(Then again, scientists who recently did some DNA study on octopuses finally reached the conclusion that they may actually be an alien life form.)
I also think it's a shame we don't produce this neurotransmitter:
N-methyl-dopamine.
N-Me-DA is the reason MDMA is so rewarding, and if you can figure that relationship out on your own, then you're smarter than most, I would say.
But, like I said last week or the week before maybe, this molecule is really all we need:
2-methylamino-1-phenylpropane.
It's a good place to start, anyway. Notice how it has no oxygen molecules anywhere in its constitution to lower its potential energy (oxidized organic compounds are basically partly like ash, which of course always has a lower potential energy than whatever was burned ["rapidly oxidized"] to produce that ash). Also, see how its basic form is supremely fat soluble and ready to cross into the brain at a moments notice, while its protonated N form is perfectly water soluble if I understand that right and ready to be absorbed by the acidic aqueous solution found in our stomachs. Finally, note how sturdy the molecule is; so sturdy, in fact, that 50% of a dose in humans is excreted unchanged in our urine. Yes, I'm on it again.
3,4,5-trihydroxyphenylethanamine.
This is the stuff of aliens, I believe.
Sound far fetched? Well, sure, but then again, some kind of octopus (and many insects and, to a lesser extent, humans as a TAAR agonist) uses octopamine:
Octopamine.
(Then again, scientists who recently did some DNA study on octopuses finally reached the conclusion that they may actually be an alien life form.)
I also think it's a shame we don't produce this neurotransmitter:
N-methyl-dopamine.
N-Me-DA is the reason MDMA is so rewarding, and if you can figure that relationship out on your own, then you're smarter than most, I would say.
But, like I said last week or the week before maybe, this molecule is really all we need:
2-methylamino-1-phenylpropane.
It's a good place to start, anyway. Notice how it has no oxygen molecules anywhere in its constitution to lower its potential energy (oxidized organic compounds are basically partly like ash, which of course always has a lower potential energy than whatever was burned ["rapidly oxidized"] to produce that ash). Also, see how its basic form is supremely fat soluble and ready to cross into the brain at a moments notice, while its protonated N form is perfectly water soluble if I understand that right and ready to be absorbed by the acidic aqueous solution found in our stomachs. Finally, note how sturdy the molecule is; so sturdy, in fact, that 50% of a dose in humans is excreted unchanged in our urine. Yes, I'm on it again.
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Dresden
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Don't worry. I have no intention of me or anyone else taking it. I just think it has the potential to be an awesome NT in a species with receptors for it, metabolic pathways to synthesize it, and brains with the necessary safeguards to protect themselves from any inherent danger possibly posed by its three aromatic hydroxyl groups. While we're on the subject, one time I saw HHMA being sold on the clear net somewhere. Does anybody have a clue what HHMA feels like if ingested? Don't worry in advance, mind you, as I have no intention of trying that one either.
HHMA.
HHMA.
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sekio
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I thought alpha-methyl dopamine was toxic; logically the N-methyl analog should be too.
Also, cachetols have horrible pharmacokinetics, phenols are generally bad enough to begin with, but by the time you get to drugs like dopamine they have to be administered as prodrugs or through IV infusions.
Also, cachetols have horrible pharmacokinetics, phenols are generally bad enough to begin with, but by the time you get to drugs like dopamine they have to be administered as prodrugs or through IV infusions.
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blueberries
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Sorry for the late reply!
So what is this mystery quinazolinone?
Plus to Dresden; Etaqualone, while being fairly similar to Methaqualone, it just doesn't hold up. It's MQ light. That's why we need to work on the basic MQ structure with slight alterations. The most slight, while increasing potency is the one in my post. It's literally the only thing I can think of without getting into nutty Japanese pharmacology, altering Afloqualone and whatnot.
My other concern however is if one does create an MQ analogue with all the same affects and a lower dose; would people pick up on it and regard it as MQ 2.0, or would they see it as just another RC? The hype would still be within MQ, no matter how good a compound you made. It could even trump MQ 1000 times over and still be almost unheard of. It's a sad age we're living in when we have better compounds than their parents but no-one gives a fuck because it doesn't have the history that the parent does. Possibly with 2C-B as the exception but still; would the average user choose 2C-B or Mescaline (hoping they're not a hippy naturist!)?
People want what's known. The RC industry is a bystander to "famous" drugs. We have better drugs and better affects from them than nearly all common drugs but we never get heard. RC is associated with untested and unknown. People fear it. "At least we know the dangers of the known drugs" What the hell?! These compounds are derived from the same structures as the known drugs, the differences (and side effects) are almost exactly the same but no matter what, they'll never gain ground and the lesser, "known" drugs will always be more popular.
In this community we can design, create and beautify these compounds but they'll never gain a foothold. That's sad. We can draw anything we like but only we can reap the benefits and we are but a tiny society. There needs to be a drastic change in our way of thinking, as a society and it will stem from us. I don't know what to do, I don't know how to start educating but if someone does then maybe, just maybe, we can have a chance at creating, cleaner, safer and overall better intoxicants that general society needs, even if they don't want it. I mean we could create a non-addictive heroin and nobody would know. That just fills me with hopelessness for modern society. I feel like a general inside a bunker before the apocalypse...and not in a good way. RANT OVER.
tl;dr: This is all fantasy. It's pointless til we turn the page in modern drug users' ideology. Find your monkey and educate them.
So what is this mystery quinazolinone?
Plus to Dresden; Etaqualone, while being fairly similar to Methaqualone, it just doesn't hold up. It's MQ light. That's why we need to work on the basic MQ structure with slight alterations. The most slight, while increasing potency is the one in my post. It's literally the only thing I can think of without getting into nutty Japanese pharmacology, altering Afloqualone and whatnot.
My other concern however is if one does create an MQ analogue with all the same affects and a lower dose; would people pick up on it and regard it as MQ 2.0, or would they see it as just another RC? The hype would still be within MQ, no matter how good a compound you made. It could even trump MQ 1000 times over and still be almost unheard of. It's a sad age we're living in when we have better compounds than their parents but no-one gives a fuck because it doesn't have the history that the parent does. Possibly with 2C-B as the exception but still; would the average user choose 2C-B or Mescaline (hoping they're not a hippy naturist!)?
People want what's known. The RC industry is a bystander to "famous" drugs. We have better drugs and better affects from them than nearly all common drugs but we never get heard. RC is associated with untested and unknown. People fear it. "At least we know the dangers of the known drugs" What the hell?! These compounds are derived from the same structures as the known drugs, the differences (and side effects) are almost exactly the same but no matter what, they'll never gain ground and the lesser, "known" drugs will always be more popular.
In this community we can design, create and beautify these compounds but they'll never gain a foothold. That's sad. We can draw anything we like but only we can reap the benefits and we are but a tiny society. There needs to be a drastic change in our way of thinking, as a society and it will stem from us. I don't know what to do, I don't know how to start educating but if someone does then maybe, just maybe, we can have a chance at creating, cleaner, safer and overall better intoxicants that general society needs, even if they don't want it. I mean we could create a non-addictive heroin and nobody would know. That just fills me with hopelessness for modern society. I feel like a general inside a bunker before the apocalypse...and not in a good way. RANT OVER.
tl;dr: This is all fantasy. It's pointless til we turn the page in modern drug users' ideology. Find your monkey and educate them.
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aced126
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People fear RC for a good reason imo. Even though RC compounds are derived from parent compounds (with established safety and efficacy), we just don't know enough molecular biology to accurately predict the effects one substitution might have. For example, an RC chemist might find it reasonable to break the methylene bond on MDA to give 3,4-dimethoxyMDA. This would be metabolised to alpha-methyldopamine which is potentially neurotoxic. You're right, most RCs have similar side effects and profiles to their parents. But you never know, just one small change to the molecule could confer it several times more potency at an undesired target. Yes, the probability of this is low, but the probability is still there. That is not to say that RCs could be better and safer drugs. Many of Nichols' compounds are way less neurotoxic than MDMA.
I guess a decent analogy would be house insurance. You pay a known price (equivalent to taking a known drug and accepting the well established risks). If you don't have house insurance, your house probably won't burn down (you probably won't experience negative effects from RCs), but in the unlikely event that it does, you are fucked. My probabilities might be out of proportion I guess but the thing is most users can't calculate the risks for themselves.
But yeah, you're right, we live in a world where people don't accept altered states of consciousness.
I guess a decent analogy would be house insurance. You pay a known price (equivalent to taking a known drug and accepting the well established risks). If you don't have house insurance, your house probably won't burn down (you probably won't experience negative effects from RCs), but in the unlikely event that it does, you are fucked. My probabilities might be out of proportion I guess but the thing is most users can't calculate the risks for themselves.
But yeah, you're right, we live in a world where people don't accept altered states of consciousness.
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