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3-halo-4-(1,1-difluoromethoxy)-5-methoxyphenethylamine/cathinone/TMA homologs?

Limpet_Chicken

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So, LC will soon be submitting 3-bromo-4-(1,1-difluoromethoxy)-5-methoxyamphetamine and the corresponding 3-bromo homolog of difluoromescaline, where bromine replaces the 3-position methoxy.

I did start a similar thread a while ago, but got few views and no feedback whatsoever. Surely somebody's going to bite on this. SOMEONE must know SOMETHING about mescaline/TMA/TMC (what I'd call the corresponding beta-ketones (if I try the cat version, it'll be in the form of the pthalimidopropiophenone, which should cleave in the stomachs acidic environment to liberate the cathinone, seeing how freakishly unstable primary beta-ketoamines can be from my experience trying, unsuccessfully to plug beta-C=O-2C-B, which one of the two attempted times actually turned into bright purple dimer on the journey from plastic pot with dry powder poured in, to adding 5ml H2O from a measuring syringe, drawing it up, it became inactive in the time between drawing up and journeying to chocolate starfish; the bk-2C-B itself was orally and intravenously (difficult in the extreme but doable if registering, pulling the syringe off the rig, holding the container with the beta-keto-2C-B close to the needle, left in the vein, then drawing up quickly and carefully reconnecting the rig to the needle. Not, in any case the most feasible mode of administration)

So, the pthalimidopropiophenone derivative, assuming there is enough aldehyde left for the cathinone, is a much more practical way to do things. Although it will of course make the time to onset and speed of comeup different from the unmodified amine, the time to onset being slower I'd imagine, and comeup being more prolonged due to gradual leaching of 3-bromo-4-(1,1-difluoromethoxy)-5-methoxycathinone into the system of the subject as the pthalimide group gets split off.

But first will be the phenethylamine or the TMA homolog (3-bromo-4-(1,1-difluoromethoxy)-5-methoxyphenisopropylamine.

It seems like 4-(1,1,1-trifluoromethyl) substitution pattern leads to extremely potent psychedelics in those phenethylamines and amphetamines where the rest of the substitution pattern of the aromatic ring corresponds to known active compounds (e.g DOTFM and 2C-TFM) and trifluoromescaline (where the para-methoxy is replaced by a difluoromethyl ether) is known to be active, IIRC at some 15-35mg or so, 60mg is reported as 'strong overdose' (https://en.wikipedia.org/wiki/Trifluoromescaline

Difluoroethoxy seems to work in the case of the difluoroethoxy homolog of 3C-E, potency is increased a little in terms of dose range being lower, and whilst its a little ambiguous (3C-E is stated to last some 8-12 hours whilst the difluoroethoxy homolog is reported as 10h) as I expected the duration sounds like its a little increased, presumably due to the fact that fluorine acts as a bioisostere of a sort of hydrogen and can only generally be removed in-vivo by means of lopping off the fluorinated part wholesale, at carbon or heteroatom bonds linking the fluorinated portion of the molecule, leaving a fluorinated fragment, or occasionally as fluoride ion, in such compounds as halothane), but usually, when fluorine is attached to carbon at least, it isn't coming off. Although this is of more importance in fluoroalkyl groups and fluoroaryls, cleavage at the ether bridge of course makes it more practical.

The ONLY instance of an electron-withdrawing substitution, a halide or otherwise, is 2-bromomescaline, which is listed in wikipedia as having a quite significantly greater Ki value by an order of magnitude, and 2-bromo-4,5-MDA which is less potent than MDA (dose listed as some 300mg)

https://en.wikipedia.org/wiki/2-Bromomescaline 513nm and 215nm at 5HT2a and 5HT1a respectively)

Nothing with a halogen, cyano, nitro etc at the 3'carbon however.

So guys, take this one apart, and throw me a bone maybe?
 
First of all, you can't look at the SAR of 2,4,5-substituted compounds and extrapolate to 3,4,5-substituted compounds because the latter dock into the 5-HT2A receptor in a different orientation compared to the former.

The known SAR of mescaline is that the C4 substituent is thought to interact with a lipophilic residue or pocket in the binding site, whereas the substituents at C3 and C5 are H-bond acceptors. The aromatic ring forms a van der Waals interaction with the aromatic ring in a Phe in the bonding site, and the amine forms a salt bridge with Asp in TM3.

So it makes sense that 3-difluoromethoxy would increase affinity because it is more lipophilic than methoxy. The 2-Br group could potentially increase affinity by strengthening the aromatic stacking interaction, or its presence could alter the orientation of mescaline in the binding pocket in a way that augments one of its interactions.

The problem with 3-halo mescaline analogs is that the loss of the 3-methoxy removes a key H-bonding interaction. The 3-Br could increase affinity a bit (similar to 2-Br) but that would likely be more than offset by the loss of the H-bond interaction.
 
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First of all, you can't look at the SAR of 2,4,5-substituted compounds and extrapolate to 3,4,5-substituted compounds because the latter dock into the 5-HT2A receptor in a different orientation compared to the former.

The known SAR of mescaline is that the C4 substituent is thought to interact with a lipophilic residue or pocket in the binding site, whereas the substituents at C3 and C5 are H-bond acceptors. The aromatic ring forms a van der Waals interaction with the aromatic ring in a Phe in the bonding site, and the amine forms a salt bridge with Asp in TM3.


So it makes sense that 3-difluoromethoxy would increase affinity because it is more lipophilic than methoxy. The 2-Br group could potentially increase affinity by strengthening the aromatic stacking interaction, or its presence could alter the orientation of mescaline in the binding pocket in a way that augments one of its interactions.

The problem with 3-halo mescaline analogs is that the loss of the 3-methoxy removes a key H-bonding interaction. The 3-Br could increase affinity a bit (similar to 2-Br) but that would likely be more than offset by the loss of the H-bond interaction.

Can you set me the source of this? It looks like quite an interesting read.
 
I was not so much attempting to extrapolate SAR from 2,4,5-subst. pattern phenethylamines and derivatives to 3,4,5-trisubstitution, as commenting/moaning that there seems to be nothing I have yet been able to find at all concerning halogens in the 3-position even having been assayed, either in vitro or in something warm and tasty, like the brain of a rat, or better yet, a human.

I was considering this one for enough potential viability in some measure because of the way that halogen bonding can closely resemble hydrogen bonding in organic systems featuring protein-ligand interactions. Halogens can form these bonds in the case of Cl, Br and I, and occasionally fluorine, according to my reading on the subject, with the bond strength being optimal in the case of iodine, and weakest in the case of chlorine (not sure where fluorine fits into this scheme), and halogen bonding is known to occur between halogens and amines, carboxylic acids and amides, which to me sounds not all too unlikely on electronic terms to be able to fill in for the missing H-bond. Whats going to happen in terms of steric considerations I'm not too sure. are phenyl, phenylmethyl, phenyl ethers or phenyl alkyl ethers tolerated at the 3-position in 3,4,5-substituted phens/amphetamines where the other groups are methoxy? or the likes of pyridine, pyrrolidine, thiophene?

And is 3- or 4-cyclopropyl or cyclopropylmethyl/cyclopropylmethoxy a known animal? Would be interesting to know, being the smallest carbon-based ring structure, for reasons of trying to work out how much steric space there is in the binding pocket for the 4-MeO (or difluoromethoxy in this case of course).

I'm not very familiar at all with salt bridge interactions, can you perhaps expound on this? and likewise the aromatic stacking. Is the latter, put simply, Van der Waals interactions between the two benzene rings of the phenyl group of the drug, and the phenylalanine residue of the receptor aligned flat plane-to-flat plane?
 
So give me a clue pls, otherwise I'm just gonna think it's to do with gaout , crystalline on ur joints . Could be wrong or it could be to do dexamethasone days :)lol
 
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Limpet_Chicken said:
I was considering this one for enough potential viability in some measure because of the way that halogen bonding can closely resemble hydrogen bonding in organic systems featuring protein-ligand interactions. Halogens can form these bonds in the case of Cl, Br and I, and occasionally fluorine, according to my reading on the subject, with the bond strength being optimal in the case of iodine, and weakest in the case of chlorine (not sure where fluorine fits into this scheme), and halogen bonding is known to occur between halogens and amines, carboxylic acids and amides, which to me sounds not all too unlikely on electronic terms to be able to fill in for the missing H-bond.

What do you mean by halogen bonding? In case of hydrogen bonds it's the other way around actually (fluorine being the strongest HBA out of all and iodine the weakest), but halides don't really form hydrogen bonds in organic compounds, actually only fluorides do to some extent, and Cl, Br, and I don't at all basically, and this has to do with the strength of C-X bond polarization. In inorganic compounds it may be different due to greater differences in electronegativity between a halogen atom and atom of other elements resulting in more polarized covalent or even ionic bonds.

That's why halides aren't good substitutes for alkoxy groups in ligands that use them for hydrogen bonding.
 
Can you set me the source of this? It looks like quite an interesting read.

McLean et al, J Med Chem 49: 4269 is one example. That paper indicates that the role of the 4-position methoxy is also as a H-bond acceptor. If that is true then modifications such as difluoromethoxy or ethoxy may be increasing affinity by reorienting the oxygen lone pairs; but it is also possible the the alkoxy group at C4 is playing multiple roles.
I was not so much attempting to extrapolate SAR from 2,4,5-subst. pattern phenethylamines and derivatives to 3,4,5-trisubstitution, as commenting/moaning that there seems to be nothing I have yet been able to find at all concerning halogens in the 3-position even having been assayed, either in vitro or in something warm and tasty, like the brain of a rat, or better yet, a human.

In general, the potential of 3,4,5-substitution is thought to be limited, at least in terms of producing compounds with reasonable potency. When that view is coupled with the fact that 3-halogen substitution would be expected to reduce affinity, most people have viewed this as a dead end.

I was considering this one for enough potential viability in some measure because of the way that halogen bonding can closely resemble hydrogen bonding in organic systems featuring protein-ligand interactions. Halogens can form these bonds in the case of Cl, Br and I, and occasionally fluorine, according to my reading on the subject, with the bond strength being optimal in the case of iodine, and weakest in the case of chlorine (not sure where fluorine fits into this scheme), and halogen bonding is known to occur between halogens and amines, carboxylic acids and amides, which to me sounds not all too unlikely on electronic terms to be able to fill in for the missing H-bond. Whats going to happen in terms of steric considerations I'm not too sure. are phenyl, phenylmethyl, phenyl ethers or phenyl alkyl ethers tolerated at the 3-position in 3,4,5-substituted phens/amphetamines where the other groups are methoxy? or the likes of pyridine, pyrrolidine, thiophene?

Halogen bonds exist but are relatively uncommon in ligand-receptor interactions and could not form in this case.

Large bulky aryloxy substituents reduce 5-HT2A affinity, or can even shift the ligands to act as antagonists because they can completely change the binding orientation.

Benzyloxy analog of DOB was made by Richard Glennon.

And is 3- or 4-cyclopropyl or cyclopropylmethyl/cyclopropylmethoxy a known animal? Would be interesting to know, being the smallest carbon-based ring structure, for reasons of trying to work out how much steric space there is in the binding pocket for the 4-MeO (or difluoromethoxy in this case of course).

Even ethoxy isn't well tolerated, so going bulkier wouldn't seem to make a lot of sense -- see papers by Nichols & Braden; also see Shulgin's tests of EMM


I'm not very familiar at all with salt bridge interactions, can you perhaps expound on this? and likewise the aromatic stacking. Is the latter, put simply, Van der Waals interactions between the two benzene rings of the phenyl group of the drug, and the phenylalanine residue of the receptor aligned flat plane-to-flat plane?

A salt bridge is an interaction where opposite charges line up in space.

Aromatic stacking is the same as van der Waals, but there are multiple physical orientations other than face-to-face.
 
I was not so much attempting to extrapolate SAR from 2,4,5-subst. pattern phenethylamines and derivatives to 3,4,5-trisubstitution, as commenting/moaning that there seems to be nothing I have yet been able to find at all concerning halogens in the 3-position even having been assayed, either in vitro or in something warm and tasty, like the brain of a rat, or better yet, a human.

I was considering this one for enough potential viability in some measure because of the way that halogen bonding can closely resemble hydrogen bonding in organic systems featuring protein-ligand interactions. Halogens can form these bonds in the case of Cl, Br and I, and occasionally fluorine, according to my reading on the subject, with the bond strength being optimal in the case of iodine, and weakest in the case of chlorine (not sure where fluorine fits into this scheme), and halogen bonding is known to occur between halogens and amines, carboxylic acids and amides, which to me sounds not all too unlikely on electronic terms to be able to fill in for the missing H-bond. Whats going to happen in terms of steric considerations I'm not too sure. are phenyl, phenylmethyl, phenyl ethers or phenyl alkyl ethers tolerated at the 3-position in 3,4,5-substituted phens/amphetamines where the other groups are methoxy? or the likes of pyridine, pyrrolidine, thiophene?

And is 3- or 4-cyclopropyl or cyclopropylmethyl/cyclopropylmethoxy a known animal? Would be interesting to know, being the smallest carbon-based ring structure, for reasons of trying to work out how much steric space there is in the binding pocket for the 4-MeO (or difluoromethoxy in this case of course).

I'm not very familiar at all with salt bridge interactions, can you perhaps expound on this? and likewise the aromatic stacking. Is the latter, put simply, Van der Waals interactions between the two benzene rings of the phenyl group of the drug, and the phenylalanine residue of the receptor aligned flat plane-to-flat plane?

A salt bridge interaction is the strongest non covalent interaction between a drug and protein, and is normally crucial to binding. If the drug has an amine moiety, it is quite likely that the amine is protonated in the binding pocket, and it forms a Coulomb type attraction with a negatively charged amino acid residue, like Asp or Glu.

In fact with aromatic stacking, 2 aryl rings parallel and facing directly towards each other actually isn't the strongest possible orientation possible. Stronger interactions are possible in edge-to-edge or parallel displaced conformations.

https://en.wikipedia.org/wiki/Stacking_(chemistry)
 
Could someone explain more about halogen bonding with respect to organic protein-ligand interactions especially, please?

Also, the wikipedia article states that iodine forms the strongest halogen bonds in the halogen bond article, not fluorine, although on the face of it it makes sense that fluorine may indeed form the strongest bonds given that halogen bonding is dependent on the relative strength of the halogen and electron donor in halogen bonding, is it the fact that the electron-withdrawing effect of a halogen, pulling away electron density, being strongly electronegative, from an aromatic ring to itself, does this result in delocalization and deconjugation of the electron 'chain' within say, a phenyl ring? and is it different in non-conjugated systems, and ones without double bonds such as aliphatic chains, and olefins where the double bond is not conjugated with the Ph ring, having a terminal alkene, or one separated from the aromatic ring? how does halogen bonding interact with allylic groups?

Also is there any online or downloadable tool I can use to calculate ionization energies, electron donor/acceptor strength and lewis acid-basicity? one that allows it for aminoacids in peptide or proteins would be even better. This is because I *cannot* now do it for myself, because of my dyscalculia, as post-nasty incident that I'd sooner not dredge up again, psychologically speaking. But long, traumatic story short, I've ended up almost acalculic. I need to use tools for every single last calculation involving numeracy for ALL my (bio)chemistry projects, even calculating 'simple' things such as molar quantities of reagents I now can't do on my own (I use a really handy little applet on the sigma-aldrich site (http://www.sigmaaldrich.com/chemist...chnical-library/mass-molarity-calculator.html)


And this: http://www.endmemo.com/chem/mmass.php

From HERE: http://www.endmemo.com/index.php (has some REALLY useful tools for all kinds of chemistry/physics/biology)

Theres nothing in the way of lewis acid/base strength though.
 
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I didn't actually refer to halogen bonding, I wasn't even aware that such a term existed and thought you meant halogen atoms forming hydrogen bonds as acceptors, now that I found out what it means, it makes sense that iodine is the most susceptible to form halogen bonds as it is the least electrophilic of all halogens aside from astatine.
 
Well I THINK we can safely leave astatine out of the picture for now. It isn't like I yet have a cyclotron to play with.

And in any case, I'll be damned if I'd swallow anything that radioactive.

And Adder, it looks like we were simply using very different definitions of halogen bonding. I'd still like to know, assuming 5HT2a is correct, the reason WHY this would or could not happen in this case, and have that bromine form a halogen bond.

Still, guys, think this has potential for (agonist) activity? in any case these are going to be submitted to a thorough poking with the ol' Shulgin-stick so we should find out whether it is in fact, active, or otherwise soon. The aldehyde is ready and waiting. This is definitely going to be one of my more interesting research projects, even if the phenethylamine, amphetamine and pthalimidopropiophenones prove inactive.


HAS this substitution pattern ever gone into something warm, squishy and nonquadrupedal? or is a first in man
 
And is 3- or 4-cyclopropyl or cyclopropylmethyl/cyclopropylmethoxy a known animal? Would be interesting to know, being the smallest carbon-based ring structure, for reasons of trying to work out how much steric space there is in the binding pocket for the 4-MeO (or difluoromethoxy in this case of course).

Yes, CPM is known....

https://erowid.org/library/books_online/pihkal/pihkal037.shtml

One of Shulgins I always really wanted to try.

I've tried 3CE once btw, and it was really nothing interesting, well actually it flat out sucked. Haven't felt like repeating it again since. But don't let that stop you from your research. ;)


....... between drawing up and journeying to chocolate starfish;
:D lol
 
Have heard 2C-E is known to be somewhat of a difficult journey.

Here's another thought. 3-Alkoxy, 3-alkylthio or the more potent 3-alkylseleno analogs lf the bromo compounds themselves be inactive, they would be ripe for transformations to such derivatives. And these should be active.

Really, really would like to know more about halogen bonding though.

And '...let that stop you'? Not going to=D
 
If your goal is just to identify active compounds then you will probably be able to do that -- anything that activates 5-HT2A with some degree of selectivity will be active.

But most investigation into hallucinogen SAR is not just trying to identify active compounds, but rather trying to figure out how to maximize affinity and potency, which is more useful information for a number of reasons. That is one of the reasons that Shulgin, Nichols, and Glennon et al were more apt to stick with the 2,4,5-substitution pattern -- the 3,4,5-substitution pattern just isn't optimal to yield high affinity binding.
 
I'd find inactive compounds interesting, although not in quite the same way as the make and taste approach with an active compound (I WON'T do animal research, not for any reason, I just do not agree with it), yes, its true I'd far sooner have an active, than inactive compound, but both can tell us things about the requirements for binding. But I really have been trying, and I cannot find even attempts at this substitution pattern (that is, the element of having an electron withdrawing group on the 3-position carbon of the phenyl, or phenyl bioisostere) in a polysubstituted phenethylamine or amphetamine. The closest I can come to is trifluoromethyl, and thats a monosubstitution in the case of fenfluramine.

I'd keep the inactive (or a sample of it, rather, sufficient to test in a raadioligand displacement assay in vitro) Granted if there prove some decently potent active compounds here in this pharmacophore, I'll run with it, depends what primary assays in man do. But only limited quantities of the aldehyde are currently available. And some of the difluoromescaline analogs do display some odd properties, such as one of them is considerably lower affinity than mescaline but displaying pretty high per os potency at much lower doses. Thats the sort of thing that intrigues me, and of course, there may well be other factors going for even a low affinity/efficacy compound of an active agonist nature, is mescaline not meant to be one of THE most rewarding psychedelics there is around? I've not yet had an active dose myself, only threshold with cactus, but its certainly on my list.

5HT2a, btw my reason for potentially going progressively bulkier, would be to probe the size of that binding pocket, and steric tolerance thereof.

And I STILL want to know as much as anyone can give me about halogen bonding.
 
I know that, I was making the comparison between the two (based on reputation, not taken either)

Its certainly interesting though how dramatically different a character can result from extension of a simple carbon chain from methyl to ethyl. (contrasting w/2C-D)

Will be trying the former soon:) (2C-D) its been high on my to-do list for a while now.


As for my opening post, I was more talking about the potential for trying out the 4-difluromethoxy analog of 3-C-E.
 
So just not much fits the description of shielded H-bond acceptor for the 3-position is the reasons why optimalizing 3,4,5 phens difficult like that? Trifluoromescaline is apparently tested as relative potent, I don't know if the difluoro was in their array and if that is more potent as said in the OP... Thioproscaline is of similar potency, but thio's have more body component usually. So potentially difluorothioescaline is pretty optimized?

I'd very much like to try that difluoromesc D:

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Sure the amphetamine analogues of the mescs may be similarly interesting, but it seems like it's a bit of a niche area one should to get experience with via 3C-E and 3C-P, it's not all that clear which has more potential - potency isn't everything - and how it compares to their 2C mesc counterparts... Is 3C-MAL good for example? That the allyl and methallyls seem to pick up from the homologue serie becoming lackluster, that possibly has to to with the electronic interactions?
So: from that very speculative rationale using fluoros instead could have such a similar impact, but for translating that to 3C's I think it's worth knowing more first about something like 3C-MAL.

Are the mesc analogues of DOTs known? Oh no this is gonna take some real digging into the Shulgin Index... Nope I see no thio's on any of those TMA's... should have been under analogues of TMA-1.

(example)

NSFW:
1-(3%2C5-dimethoxy-4-propylthio-phenyl)propan-2-amine.png

1-(3%2C5-dimethoxy-4-(2%2C2-difluoroethyl)thio-phenyl)propan-2-amine.png
 
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Its more likely that the phenisopropylamine of this compound is going to be tested first, partly due to the greater availability of nitroethane vs nitromethane (can be got easily enough, its just that one is on the shelf whilst the other must be bought or made) and in the case of the corresponding TMA analogue potency is liable to be greater than that of the phenethylamine, so small scale testing is of more value in that it consumes less of a not very available benzaldehyde and should the amphetamine turn out inactive then its more than likely that the phenethylamine would too be inactive. Leaving the remainder of the aldehyde for use of substitution of the aryl bromide for alkoxy or alkoxythio.

Difluoromescaline is known to be active in the rodent head-twitch assay and is significantly more potent than mescaline, I don't have the paper on this machine and cannot access the one that does have it currently, IIRC its somewhere in the region of being equipotent to 3C-P. It'll likely as not be tried, as would 4-difluoromethoxy-TMA should either the 3-brominated amphetamine prove a non-starter with regards to in-vivo activity or should any more of the aldehyde prove possible to obtain. Although the latter, would be difficult.
 
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