I Like to Draw Pictures of Random Molecules

[Hodor]

What's the deal with Bromine, from a biochemical standpoint? Why is it so prevalent in psychoactive chemicals?

Bromine is both electronegative (i.e. it draws in electrons, which may be important for interacting with receptors), and relatively large (which can greatly affect a drug's potency). It is also relatively easy to both attach to and selectively detach from a molecule, meaning you can easily synthesize a brominated compound *and* use it as a precursor for e.g. a chlorinated compound.

However, I wouldn't say that it is all that "common" in psychoactives. Sure, for the reasons mentioned above it is basically "perfect" for the 4-position in a psychedelic phenylethylamine (so you've got DOB, as well as its analogues 2C-B, 2C-B-FLY, 25B-NBOMe, and so on), but as far as other psychoactives are concerned, bromine is probably rarer than chlorine (note: fluorine, chlorine, bromine and iodine form a group of very reactive elements called "halogens" that play an important role in Organic Chemistry).

There's been relatively little interest in brominated tryptamines, for example.

With many "legal highs" or "research chemicals", people will even deliberately use fluorine instead of other halogen substituents like bromine because it is such a *small* molecule - para-Fluoro versions of fentanyl analogues, for example, probably aren't going to differ from their parent molecules all that much as far as potency and toxicity are concerned.

 

[aspiringdrugdesign]

Differently positioned serotonin/racetam mashup

Could also try this if you want the ethanamine branch to go the other way

Benzothiobut, using benzothiophene as a bioisostere

More silane derivatives, I don't know if these would work

 

[Hodor]

Also is it prevalent? Compared to what?

Yeah, I should perhaps stress this point again:
Bromine is easily among the top ten elements found in psychoactive drugs, sure.

However, that is because psychoactive substances are almost always organic compounds, which *severely* limits the number of elements you're dealing with.

The various psychoactive organics found in nature are usually made up of just 3 or 4 elements, ex.:
DMT: carbon, hydrogen, nitrogen
THC: carbon, hydrogen, oxygen
morphine: carbon, hydrogen, nitrogen, oxygen

Sulphur and phosphorous are also pretty useful in organic chemistry at times, although phosphorous is relatively rare in psychoactives for various reasons.

Lastly, you've got a group of elements called the halogens (which bromine belongs to), which are less commonly found in natural substances, but tremendously valuable when designing synthetic compounds.

Virtually all the other elements suffer from concerns like toxicity and/or a diminished ability to form stable covalent bonds, which mostly rules them out as building blocks for psychoactive substances that anyone would actually ingest willingly.

So basically out of the ~120 known elements you've got just 10 that you'll realistically see in a psychoactive drug, and out of those, bromine is probably in the bottom 5.

 

[aspiringdrugdesign]

This one is inspired by kynurenic acid, which has some downstream effects on some of the neurotransmitters -- it also binds to some receptors but I forgot which.

I figured since it indirectly impacts dopamine, perhaps this would do something.

Some thioamph inspired phenylpiracetam molecules, and unless I'm mistaken, those acetyl groups on the right would metabolize into hydroxyl groups

Did someone say 5-HT2A agonism?

I'm curious if an n-thiophene function would work similarly, or not in this situation

 

[Hodor]

Did someone say 5-HT2A agonism?

Ralf Heim - the guy who discovered the NBOMe‘s - synthed & assayed both the 2C-x-NBOMe‘s and their DOx-NBOMe analogues.

Interestingly, the combination of an N-methoxybenzyl and an alpha-methyl-group didn’t seem to result in increased receptor affinity when compared to the plain 2C-x-NBOMe version.

 

[aspiringdrugdesign]

Ralf Heim - the guy who discovered the NBOMe‘s - synthed & assayed both the 2C-x-NBOMe‘s and their DOx-NBOMe analogues.

Interestingly, the combination of an N-methoxybenzyl and an alpha-methyl-group didn’t seem to result in increased receptor affinity when compared to the plain 2C-x-NBOMe version.

Interesting, I knew the alpha methyl group doesn't do much for 5-HT affinity, but I was basing this off of bromo-dragonFLY. Perhaps something about those furan groups would cause the n-benzyl functions to have more affinity than its counterparts

2CBCB-hemiFLY-NBOME

Some opioid antagonists I thought of

I don't think this would do much but hybrids are fun to make

 

[aspiringdrugdesign]

This isn't the thread to ask KDazzle

 

[Nagelfar]

Yeah, I should perhaps stress this point again:
Bromine is easily among the top ten elements found in psychoactive drugs, sure.

However, that is because psychoactive substances are almost always organic compounds, which *severely* limits the number of elements you‘re dealing with.

The various psychoactive organics found in nature are usually made up of just 3 or 4 elements, ex.:
DMT: carbon, hydrogen, nitrogen
THC: carbon, hydrogen, oxygen
morphine: carbon, hydrogen, nitrogen, oxygen

Sulphur and phosphorous are also pretty useful in organic chemistry at times, although phosphorous is relatively rare in psychoactives for various reasons.

Lastly, you‘ve got a group of elements called the halogens (which bromine belongs to), which are less commonly found in natural substances, but tremendously valuable when designing synthetic compounds.

Virtually all the other elements suffer from concerns like toxicity and/or a diminished ability to form stable covalent bonds, which mostly rules them out as building blocks for psychoactive substances that anyone would actually ingest willingly.

So basically out of the ~120 known elements you‘ve got just 10 that you‘ll realistically see in a psychoactive drug, and out of those, bromine is probably in the bottom 5.

So much more could be done with the transition metals than is; for constraint of the cost and specificity in the synthesis is my guess why it's not though. Speaking strictly of chelates and such; i.e. bioorganometallic chemistry

 

[aspiringdrugdesign]

So much more could be done with the transition metals than is; for constraint of the cost and specificity in the synthesis is my guess why it's not though. Speaking strictly of chelates and such; i.e. bioorganometallic chemistry

Could you give a few examples of transition metal containing drugs? Any nootropics or psychoactive ones? I think I've seen a few used for treating specific cancers, but I don't know enough on the subject

 

[Hodor]

Could you give a few examples of transition metal containing drugs? Any nootropics or psychoactive ones? I think I've seen a few used for treating specific cancers, but I don't know enough on the subject

Apparently someone made a more potent version of troparil (itself a structurally simplified version of cocaine) using a benzene-chromium-tricarbonyl complex instead of plain phenyl.

The structural configuration of this complex has been called a "piano stool" for rather obvious reasons:

Obviously more of a "proof of concept" than something we might realistically see as grey-market a designer drug, but extremely interesting nonetheless.

 

[Solipsis]

Good clarification about the bromine there

I think alpha-methyl NBOMe's not being so good is for similar reasons as tryptamine-NBOMe's happening to not be good or antagonistic (IDK if some DOX-NBOMe's are antagonistic): the NBOMe group enhances a particular conformation of 2C-X and there is no reason why this necessarily translates to all kinds of - even closely related - agonists which may have a different spatial conformation in the receptor. The way they bind spatially may be mutually exclusive so finding an optimum tends to be a custom job. To say whether other NBOMe's pretty much couldn't (have been) good depends on that binding conformation of the parent molecule and it has to be compatible. I've seen some of those conformations of different psychedelics and some are surprisingly different, though I am not 100% sure about whether those were produced by notoriously unreliable computational models.

@ the thiophene analogue: I think it has a good chance of working fine though likely not a first-class one like a lot of NBOMe's but a second-class like NBOHs or worse. Similarly isn't there a THF analogue?

Chromium doesn't seem viable for a drug due to toxicity? Aren't there any Fe ones?

 

[aspiringdrugdesign]

Apparently someone made a more potent version of troparil (itself a structurally simplified version of cocaine) using a benzene-chromium-tricarbonyl complex instead of plain phenyl.

The structural configuration of this complex has been called a "piano stool" for rather obvious reasons:

Obviously more of a "proof of concept" than something we might realistically see as grey-market a designer drug, but extremely interesting nonetheless.

Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?

I think alpha-methyl NBOMe's not being so good is for similar reasons as tryptamine-NBOMe's happening to not be good or antagonistic (IDK if some DOX-NBOMe's are antagonistic): the NBOMe group enhances a particular conformation of 2C-X and there is no reason why this necessarily translates to all kinds of - even closely related - agonists which may have a different spatial conformation in the receptor. The way they bind spatially may be mutually exclusive so finding an optimum tends to be a custom job. To say whether other NBOMe's pretty much couldn't (have been) good depends on that binding conformation of the parent molecule and it has to be compatible. I've seen some of those conformations of different psychedelics and some are surprisingly different, though I am not 100% sure about whether those were produced by notoriously unreliable computational models.

Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups. I read something about the NBOMe moiety working through pi-stacking interactions. What does that actually mean? Is it similar to hydrogen bonding?

@ the thiophene analogue: I think it has a good chance of working fine though likely not a first-class one like a lot of NBOMe's but a second-class like NBOHs or worse. Similarly isn't there a THF analogue?

I wish there was a program or app that could accurately calculate receptor affinities given a molecule -- that'd be very useful

If I'm guessing correctly, a THF analog would participate in hydrogen bonding, right? Although it wouldn't be conjugated like a benzene or thiophene ring as there's no pi electrons there. (unless you aren't referring to tetrahydrofuran?)

Is there much info on that thiophenyl group for phenethylamines? I pulled it off Aleph-6, and there's another phenethylamine I found named 3C-BZ. 3C-BZ has an oxygen in place of the sulfur, however both 3C-BZ and Aleph-6 have much longer durations than their non-thiophenyl/phenol group counterparts. Does it impact metabolization in some manner?

 

[Tzcatlipoca]

Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?




Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups. I read something about the NBOMe moiety working through pi-stacking interactions. What does that actually mean? Is it similar to hydrogen bonding?



I wish there was a program or app that could accurately calculate receptor affinities given a molecule -- that'd be very useful

If I'm guessing correctly, a THF analog would participate in hydrogen bonding, right? Although it wouldn't be conjugated like a benzene or thiophene ring as there's no pi electrons there. (unless you aren't referring to tetrahydrofuran?)

Is there much info on that thiophenyl group for phenethylamines? I pulled it off Aleph-6, and there's another phenethylamine I found named 3C-BZ. 3C-BZ has an oxygen in place of the sulfur, however both 3C-BZ and Aleph-6 have much longer durations than their non-thiophenyl/phenol group counterparts. Does it impact metabolization in some manner?

Great post! Let me begin with thank you! I theorize since sulfide/sulfamide groups are recognized by the body as poison/vile, they may have priority of excretion as a radical group over oxygen which is considered fuel for the cells. In order to prove this, a selenide in the radical group of popular psychedelics should be designed and tested as selenium is the ultimate antibody. In theory selenide compounds should have metabolic over the sulfide compounds. How this would contribute to activity and subjective tripping, I have no idea..
Food for thought..

Best regards,
Tezcat

 

[Hodor]

Very interesting, I wonder how metabolization works with coordination complexes. I actually don't even get how the "piano stool" is bonded to the benzene ring. (it's not bonded to the center, is it?) How does that work?

Well, the benzene isn't "bonded to" the piano stool because it is part of the piano stool - it's supposed to be the seat.
I mean, you know what a piano stool looks like, right?

The seat is the benzene, the angled legs are the carbonyls, and the metal is sort of the part where the vertical rod joins the angled legs... so basically, the metal sits below the center of the plane of the benzene ring, with the metal's d-orbitals interacting with the benzene's pi-electrons.

In an ordinary "sandwich complex" the metal is, well, "sandwiched" between two aromatic ligands (the prototypical "sandwich" is the ferrocene molecule). (Benzene)chromium tricarbonyl is a "half-sandwich" complex, in which the chromium sits between an aromatic ligand (which is haptic, i.e. it bonds to the metal with multiple contiguous carbon atoms) on one side, and several unidentate ligands (which only bond with one atom each) on the other.

Huh, I didn't realize that NBOMe groups were for 2Cs only! I figured it'd be applicable to a majority of phenethylamine 5-HT2A agonists, although there'd obviously be a few that don't work because of other functional groups.

I just looked at Ralf Heim's dissertation again, and apparently he actually synthed 2C-B-FLY-NBOMe, 2C-B-FLY-NBOH, as well as the alpha-methylated DOB-FLY-NBOMe, and assayed their activity on rat 5HT2A receptors. Potency-wise, the former two were roughly in the same ballpark, while the alpha-methylated version was significantly less active. He also compared (among others) DOB, 25B-NBOMe and DOB-NBOMe, with DOB-NBOMe being about as potent as plain DOB, and significantly less potent than 25B-NBOMe.
http://www.diss.fu-berlin.de/diss/s...000001221/3_RalfHeimPharmakologischerteil.pdf (in German)

Of course this is a 14-year-old in-vitro study on rat receptors, so take these results with a grain of salt.

 

[Solipsis]

Benzofurans (and I guess benzodifurans) are supposed to be heavy on the liver right? I was pretty concerned when people started trying 2C-B-FLY-NBOMe not that long ago, in general. Fortunately for the liver problems the dosage is so incredibly low.

Anyway: with regards to the 2C-T-X benzodifuran crossover above and its potential non-NBOMe analogue I would personally be really careful. 2C-T's have an incredibly complex metabolism already where there are signs that metabolites may play a role in both the activity and potential toxicity and interactions. Not sure you want to introduce extra challenges for e.g. the liver and perhaps inhibit parts of the metabolism with who knows what consequences. 2C-T's are a hit or miss anyway with GI problems, in my opinion you want to keep all interactions to a minimum when dealing with 2C-T's including with minor things you might not even really consider but which do matter for what your liver enzymes are up to.
Staying unusually clean and healthy might just help to get a good 2C-T-X trip. I stilll have some T-7 which I love so much. Too bad the dose-response curve can be so all over the place!

Sorry I have no molecules for you but I do like that pianochair, have had some good experiences on that.

 

[sekio]

from earlier

 

[Swerlz]

Did Shulgin ever look into the 3,5-dimethoxy-4-haloPEAs? We all know the 2,5's were good to go and i know he looked into the amphetamine 3-methoxy homolog of DOB but can't see any PEA research on the matter

Example:

 

[Tzcatlipoca]

For a good introduction try flipping through PiHKAl and TiHKAL, pay attention to the dosage/activity with respect to the structure of the molecule.

Will continue doing immediately.
Thank you,
Tez

 

[LucidSDreamr]

i would be curious to search some of these on scifinder but havn't done so. I wonder if they have been explored

 

[Swerlz]

i would be curious to search some of these on scifinder but havn't done so. I wonder if they have been explored

http://www.bluelight.org/vb/threads/504286-PCP-analogs-(Cumulative)

1-(1-phenylcyclopentyl)piperidine

The substance wasn't even synthesized. Any enlargement (or the contrary action) of the cyclohexane ring gives a massive decrease in activity, so no further research makes sense.