How do you design new theoretical drugs

[Mabeydrug]

I have been looking through the forum and found a thread about a theoretical mdma alternative. I found this interesting and wondering how you first draw them and how to design them to fit the effects you want. Sorry if my English is bad or i have posted it on the wrong thread.

 

[clubcard]

1)Methamphetamine - open chain dopamine/norepinephrine transport ligand.
2)Desoxypipradrol - semi rigid dopamine/norepinephrine transport ligand.
3)Nomifensine - rigid dopamine/norepinephrine transport ligand.
4)(6R,10bS)-rel-1,2,3,5,6,10b-Hexahydro-6-phenyl-pyrrolo[2,1-a]isoquinoline - high affinity, chiral, rigid dopamine/norepinephrine transport ligand.

If you look at all 4, you can see that the PEA (phenylethylamine) moiety is in all of them. Buy ChemOffice or just a ball & stick DIY kit to see how they overlay. Note that nomifensine IS chiral but the (more) active isomer isn't available. That is just about the simplest example. A (substituted) benzene ring, 2 methylene (-CH2-) spacer and basic nitrogen. Triple releaser/reuptake inhibitors normally need something in the para (4) position of the benzene ring. AFAIK nobody has tried adding a p-Me to 2,3 & 4. It is convenient because the body can easily metabolize it, unlike the halogens & pseudohalogens. The p-NO2 is totally unknown, as far as I can tell. It is an intermediate so find the patent.

Ask yourself who is the most important person in YOUR world and ask yourself 'would I be happy for that person to ingest my design?' and the answer NO is my answer. It is technically interesting but doing it professionally takes years. If it were just for me, I would go for the (S) isomer of DON. Shulgin mentions the chiral DOB & DOM so go for the one that DOESN'T bind to the 5HT2a receptors, the one that might just be high-affinity transport.

 

[Hodor]

I have been looking through the forum and found a thread about a theoretical mdma alternative. I found this interesting and wondering how you first draw them and how to design them to fit the effects you want. Sorry if my English is bad or i have posted it on the wrong thread.

If clubcard's post was a bit too hard to understand, I'll try putting it in more "layman-friendly" terms:

This is amphetamine:

Amphetamine is a "noradrenaline-dopamine releasing agent", producing pure stimulant effects. To produce the "rolly" feeling people love about MDMA-like drugs (so-called "empathogens"), we also need our drug to release serotonin. Now, from looking at the effects of other amphetamines, we have a rough idea about the SAR, or "structure-activity-relationship" of this class of drugs.

Look at the hexagon-thingie on the left of the molecule. This is called a "phenyl ring". By examining the effects of related drugs, we know that adding stuff to the bottom left corner (the "4"- or "p"-position) causes it to release greater amounts of serotonin vs dopamine and noradrenaline. However, many of these related drugs are either not all that "fun" (because there's no longer enough dopamine being released), or they have really bad side effects (like acting as MAO inhibitors, or being just plain toxic to your brain cells). Adding stuff to the top left corner of the ring (the "3"- or "m"-position) can also make it release serotonin, but this time it might be that you're releasing enough dopamine and not enough serotonin.

So you might think about adding stuff to both corners, but this might make the molecule too bulky to perfectly interact with your neurons. So finally, you stumble upon the idea to add an oxygen molecule to both the 3- and the 4-position, and connect them with a methylene group, giving you the 3,4-Methylenedioxy-bridge.

This is MDMA, or 3,4-MethyleneDioxyMethAmphetamine

Note how it has not just the 3,4-MD bridge, but also an N-methyl group (hence "methamphetamine"). If we had only added the MD bridge, we'd have MDA, which doesn't just release the desired amount of the neurotransmitters we want, but also has a potentially unwanted side-effect: It is psychedelic/hallucinogenic, making it fairly unpredictable. However, we know that an N-methyl group can decrease the psychedelic activity of various related substances, and the same goes for MDMA, which is why it is pretty much perfect at what it does.

So if we wanted to find a legal substitute for MDMA, we'd have to keep looking at related illegal substances, and try and figure out which changes to the structure result in which changes to the effects (hence "structure-activity-relationship"), but there is no guarantee that the structure we'd come up would actually be good, so some unfortunate lab rat or brave/stupid human would have to try it to see if it actually has the expected effects.

 

[clubcard]

Sub nM

(±)-McN 5652 ((6R,10bS)-rel-1,2,3,5,6,10b-Hexahydro-6-[4-(methylthio)phenyl]-pyrrolo[2,1-a]isoquinoline)

The above has a similar serotonin:noradrenaline:dopamine ratio as 4-MTA with Ki values of 0.68, 2.9 and 36.8 nM respectively but I'm pretty sure Dr Dave mentioned that the racemate was a MAOI, that would be vital when looking at this scaffold. I'm prepared to bet that the p-Me analogue would have a more MDMA-like ratio but I also don't think you can throw an MD ring onto it. MAYBE a benzofuran would work (nice aromatic ring so the O is planer, an MD ring will adopt the minimum-energy i.e. wrong conformational isomer) but it's one hell of a jump. Sure, 'it might be great' but equally 'sure someone will get hurt'.

I'm more interested in the fact that it has sub-nM affinity and a decently high cLogP (rules of 5). I think people really do need to be responsible about what they post as I KNOW bread-heads who pick up a compound, let people here run with the ball i.e. all of theoretical research has been done and fire off orders to China, India or wherever for samples. Just imagine if a novel compound turned out to be another TGN1412 or even worse, another thalidomide. Can we predict intercalation? Well, unless you are working with Huntingdon Life Science (or similar), you have no approximation of chronic damage. Ketamine bladder syndrome anyone?

It can be fun to play with ideas; quite enough to bet someone else's life on your (or my) guesswork.

 

[Volsam]

I think historically people have been studying well-known folk effects of natural (non-synthesized by man) drugs, such as natural toxins and poisons, and as the molecular chemistry evolved, it allowed to build the structures and analyze what parts of the molecule might be responsible for certain effects.
Thus I think psychedelic phenethylamine structures come from Mescaline, tryptamines from DMT and Psylocybin, MDMA from safrole, myristicine or similar, e.t.c.

A lot of times, properties of drugs are discovered by accident, surprising the "creator". It sure is an interesting topic 8)

 

[LucidSDreamr]

look up structure activity relationship on wikipedia, should give some good background on the science behind it

 

[Hodor]

I think historically people have been studying well-known folk effects of natural (non-synthesized by man) drugs, such as natural toxins and poisons, and as the molecular chemistry evolved, it allowed to build the structures and analyze what parts of the molecule might be responsible for certain effects.
Thus I think psychedelic phenethylamine structures come from Mescaline, tryptamines from DMT and Psylocybin, MDMA from safrole, myristicine or similar, e.t.c.

A lot of times, properties of drugs are discovered by accident, surprising the "creator". It sure is an interesting topic 8)

Yep. My amphetamine=>MDMA example was not intended to describe the way Shulgin actually arrived at MDMA through rational drug design, but rather a hypothetical scenario in which you'd know about the activies of serotonergic amphetamines like PMA, 4-FA, Fenfluramine, 3,4-DMA, DOM and N-methyl-DOM, and were trying to design an empathogen with massive serotonin release, moderate stimulation and mild psychedelic effects.

In reality, Shulgin set out to create a more potent form of mescaline (alpha-methyl-mescaline or TriMethoxyAmphetamine), and since that could be made from an essential oil, he presumably started investigating other methoxylated essential oils that could be turned into psychoactive substances (the so-called "10 essential amphetamines").
While the desired lead compound for the development of high-potency phenylethylamine psychedelics was found in TMA-2 (2,4,5-TriMethoxyAmphetamine, which later evolved into the even more potent DOM), the distinctly empathogenic effects of MDA (and even more so MDMA) probably came as a surprise to him.

Shulgin didn't seem to be a fan of complex SAR models, and worked mostly via trial&error, or "make 'em & taste 'em".

 

[adder]

(±)-McN 5652 ((6R,10bS)-rel-1,2,3,5,6,10b-Hexahydro-6-[4-(methylthio)phenyl]-pyrrolo[2,1-a]isoquinoline)

(...) I think people really do need to be responsible about what they post as I KNOW bread-heads who pick up a compound, let people here run with the ball i.e. all of theoretical research has been done and fire off orders to China, India or wherever for samples. Just imagine if a novel compound turned out to be another TGN1412 or even worse, another thalidomide. Can we predict intercalation? Well, unless you are working with Huntingdon Life Science (or similar), you have no approximation of chronic damage. Ketamine bladder syndrome anyone?

It can be fun to play with ideas; quite enough to bet someone else's life on your (or my) guesswork.

I totally agree, I brought this up in one recent thread on 5-HT1A agonists as potential designer anxiolytics. IMO that's a very bad idea to open up an alternative market of drugs that never made it past the lab, to say nothing of animal studies which aren't a good indicator of safety either (look up already mentioned TGN-1412).

 

[clubcard]

Yes - Interesting that adder has come to the same conclusion. Yes we can make & taste... but just because WE didn't die is not a sign of intrinsic safety. If you do make & taste, Dr. Dave will take on board your data and alert to risks but he stays within US laws and that is very important. We can send QSAR data and he can give you a good reason NOT to make something but his position is simple 'BE CAREFUL!'. He really underlined that. Maybe in future the input WILL be of benefit to people but I don't have the billions to launch a trial.

Oh yes - I HAVE used Huntingdon Life Science for trials and you can burn through $1 million in about 6 weeks. The stuff wasn't safe but guess what? It was STILL worth the money.

 

[Hodor]

(±)-McN 5652 ((6R,10bS)-rel-1,2,3,5,6,10b-Hexahydro-6-[4-(methylthio)phenyl]-pyrrolo[2,1-a]isoquinoline)

The above has a similar serotonin:noradrenaline:dopamine ratio as 4-MTA with Ki values of 0.68, 2.9 and 36.8 nM respectively but I'm pretty sure Dr Dave mentioned that the racemate was a MAOI, that would be vital when looking at this scaffold. I'm prepared to bet that the p-Me analogue would have a more MDMA-like ratio but I also don't think you can throw an MD ring onto it. MAYBE a benzofuran would work (nice aromatic ring so the O is planer, an MD ring will adopt the minimum-energy i.e. wrong conformational isomer) but it's one hell of a jump. Sure, 'it might be great' but equally 'sure someone will get hurt'.

Wait, are you suggesting that this compound would be empathogenic?
Because I was under the impression that while noradrenaline-dopamine reuptake inhibitors and noradrenaline-dopamine releasing agents can both work as stimulants (ex.: MDPV and methamphetamine both being potent stimulants), empathogenic effects can only be induced by serotonin release, but not serotonin reuptake inhibition (ex.: SSRA's like MDAI are empathogenic, SSRI's like Citalopram aren't).

McN 5652 would likely function solely as a reuptake inhibitor, right? Sure, SNDRI's can obviously be recreational - cocaine probably being the best example - but I'm not sure whether the serotoninergic action is what makes cocaine so much more recreational than the average NDRI, or whether cocaine analogs with a stronger serotonergic action would actually feel empathogenic.

Anyway, I'm obviously not suggesting that people follow Shulgin's example and just start making & tasting compound after compound. Shulgin was probably well aware that he was taking risks, and would carefully titrate his dosages. He was certainly no "bath salt"-head who would just snort a few hundred mg's of 4,4-Dimethylaminorex, or blindly trust that Chinese lab to correctly synthesize the relatively harmless 2C-B-FLY and not confuse it with the 20 times as potent Bromo-DragonFLY. The doses you see in PIHKAL and TIHKAL usually tend to be very conservative - Shulgin lists the dose range for 4-HO-MET as 10-20mg, while it is not uncommon for today's psychonauts to take more than 40 mg.

 

[clubcard]

I am suggesting that the pyrrolidine ring confirs sub-nM affinity for one class of VMAT-2 transports and the list I went through was more or less how McN 5652 was arrived at. That it reverses depression in animal models in which tetrabenazine was used to lower 5HT is in the papers. That the patents offer the minimal amount of data to provide legal protection is as much as you get. That the QSAR mimics the PEAs is kind of hidden - that it has antidepressant activity is the important LEGAL aspect. When you go through all of the patents and papers leading up to it is why I suggested that the relative monoamine affinity can be changed is shown by 40+ years of patents and papers.

The BUT is that we have no data on anything apart from very basic animal models. Any Shulgin wannabeez can microscale their own but for people who have been through the development cycle (like adder), it is a bridge too far. While everything might LOOK good, we have no way of knowing the inherent acute or chronic risks. That is why even with HUGE amounts of screening, bad medicines still keep entering the market. Would I risk my own life? Maybe. Would I risk the lives of others. NO. That is the reason I selected this compound, truth be known. It would take a great deal of money and effort to scale the synthesis. It isn't data of value to clandestine labs. Dr Dave learned the lesson the hard way by 4MTA and as his peers grow older, we kind of see his POV. While the Chinese are good at many things, scaling novel synthetic strategies is not amongst them.

The [11C]-(+)-McN5652 enantiomer is used in functional PET scans for the VMAT-2 ligand inferring that in animal models at least, it does the job required of it. It also suggests that the other 3 isomers 'dirty' the picture. This is of interest because the more active isomers of MDA & MDMA differ. While I'm confident in predicting that the cis isomers are the more active (of interest in and of itself), between the two has differences. Indeed, between the 4. Now, if you select an appropriate p-substitution that the body can metabolize (p-Me or p-NO2 as I suggested) then it would be of interest.

The point being that the pyrrolidine ring juusssttt moves the position of the nitrogen's lone-pair. THAT is why it is interesting. Rigid, high-affinity, chiral activity known and understood. I don't have any cLogP or pKa data handy but if someone wants to draw them and shove them through ChemOffice then I suspect it will have a cLogP of >3.5>x>5.2 and a pKa at pH 7.32 of >80%. I could be totally wrong but a lot of alkane and aromatic going on compared with just 2 lone-pairs.... The benzofuran is just convenient in placing the O lone-pair planer to the ring. The down-side is that the liver forms epoxides... and epoxides are more or less going to lead to a lot of yellow cards if not a lot of RED (dead) cards. If you are not familiar with this issue, read up on beta-blockers. And COX-2 inhibitors, And thalidomide, And reboxatine, And PM(M)A. An awfully large number of unknowns.

At the very least I would be getting both blood and urine samples GCMSed of your own body after exposure. Then think if only 0.1% of people have a bad reaction, is that OK?