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Author: Subject: speculation on a homologous series to the DOx compounds
eleusis-borodin
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[*] posted on 25-2-2015 at 07:20
speculation on a homologous series to the DOx compounds


My idea is to use the 2-aminoindane skeleton in an analogous way to how the amphetamine skeleton is used in the 2,5-dimethoxy-4-(x)-amphetamine (DOx) series.

My idea is to add a methoxy group to positions 4 and 7 of the 2-aminoindane molecule, and then add an alkyl chain or halogen atom to its five position.

So lets say we put a bromine atom at position 5, we would have:

"4,7-dimethoxy-5-bromo-2-aminoindane"

I suspect this compound would be a 2,5-dimethoxy-4-bromo-amphetamine analogue.

If these methoxy groups were put on positions 4 and 7 of 2-aminoindane and either an alkyl chain or halogen atom was added to the 5 position, you would have created a homologous series of the 2,5-dimethoxy-4-(x)-amphetamines.

This is all just speculation of coarse, and in reality such substitutions may be very difficult to achieve, and there's nothing to say the end result would even be analogous in action to the DOx series, though off the top of my head it seemed plausible, and on paper the molecules look like DOx molecules only the alpha-methyl has become part of a 5 membered ring, which loops back to the benzene ring.



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[*] posted on 25-2-2015 at 07:41


Are you interested in the synthesis or how well the compound would fit into the pharmacophore model, QSAR estimates, etc.?
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[*] posted on 25-2-2015 at 07:48


There are a lot of RCs based on this already, some of them even made it into state legislation here. Might want to check what directions other people have taken.
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[*] posted on 25-2-2015 at 09:31


Yeah, not novel at all. I have actually done a little serotonin receptor work, and see that
the exact compounds you're "speculating" on have been discussed in a few places in the literature. I'm looking at references and a monogram of sorts right now from some big names in the field. I would not be able to stress enough having professional toxicologists on staff, regardless of how professionally trained anyone is in pharmacology, neuroscience, etc. Drug development takes a lot of people.

There isn't really any toxicological data on these compounds as they were never intended for human consumption, but are receptor probes. Not something anyone needs to fiddle around with outside a professional setting, and not new ground, so I am not sure where the interest derives from other than either administration or sale.
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[*] posted on 26-2-2015 at 06:53


Quote: Originally posted by Etaoin Shrdlu  
There are a lot of RCs based on this already, some of them even made it into state legislation here. Might want to check what directions other people have taken.


All of the RCs based off of this molecule have been aimed at creating molecules analogous to amphetamine or MDMA, ive seen a lot of variations of 5,6-MDO-2-AI, but as for attempting to create a homologous series of the 2,5-dimethoxy-4-x-amphetamines, nothing even close to this has ever been on the "RC" market, and in the academic community I was only able to locate 2 research papers concerning 4,7-dimethoxy-5-substituted-2-aminoindane compounds.

Again, I happened to come across some info on 2-aminoindane, and thought to myself, with some cleaver substitutions this compound could be used to create a homologous series of the DOx compounds. That's litterally all the thought I put into this before I posted.

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[*] posted on 26-2-2015 at 07:09


This is all just speculation of coarse, and in reality such substitutions may be very difficult to achieve, and there's nothing to say the end result would even be analogous in action to the DOx series, though off the top of my head it seemed plausible, and on paper the molecules look like DOx molecules only the alpha-methyl has become part of a 5 membered ring, which loops back to the benzene ring.

As for your concerns chemosynthesis, I figured these last lines of my original post (above) explained enough for others to glean that this was speculation, and not anything I had put any real thought into, playing with potential molecules on paper is a hobby of mine, and the fact the researchers in the real world have actually done some of this work proves to me that it was a good idea.



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[*] posted on 26-2-2015 at 08:00


Quote: Originally posted by eleusis-borodin  


As for your concerns chemosynthesis, I figured these last lines of my original post (above) explained enough for others to glean that this was speculation, and not anything I had put any real thought into, playing with potential molecules on paper is a hobby of mine, and the fact the researchers in the real world have actually done some of this work proves to me that it was a good idea.



-E. Borodin

I'm not trying to be argumentative, but just because something has been done doesn't make it "good." It's just a molecule. Legitimate researchers don't view drug discovery and design in terms of good or bad. We view it in terms of efficacy and tolerance/safety. Changing a molecule or physicochemical characteristics, and the subsequent pharmacological attributes associated with it, doesn't have any inherent subjective value to it. It just changes objective characteristics such as elimination, specificity, etc.

I don't want to diminish your interest in playing with molecules on paper, but it isn't comparable with legitimate pharmacology and if you had data associated with these, you'd see some very mixed results in animal models, which don't always transition well to human subjects. The lack of toxicological data should be alarming to anyone reading who wants to utilize these for human use, which is likely the kind of individual to read this subject. Both molecules you speculated on (existence? not sure what the speculation actually was... seemed to be actual psychotropic activity), both have been described, and a lack of thought before posting is kind of an odd admission to make before confirming a bias at having a good idea. From my perspective, the utility of these compounds is as a receptor probe due to their more rigid structure than more prototypical DOx compounds, and nothing more. Seeing the lack of trial data, others in the field seem to agree.
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[*] posted on 26-2-2015 at 15:47


Quote: Originally posted by eleusis-borodin  
Quote: Originally posted by Etaoin Shrdlu  
There are a lot of RCs based on this already, some of them even made it into state legislation here. Might want to check what directions other people have taken.


All of the RCs based off of this molecule have been aimed at creating molecules analogous to amphetamine or MDMA, ive seen a lot of variations of 5,6-MDO-2-AI

You're right, my error, I was remembering something with a methylenedioxy ring. This book may be of some interest, perhaps.

Quote: Originally posted by eleusis-borodin  
Again, I happened to come across some info on 2-aminoindane, and thought to myself, with some cleaver substitutions this compound could be used to create a homologous series of the DOx compounds. That's litterally all the thought I put into this before I posted.

Yes that was clear, which is why I didn't give much thought other than "seen a lot of amphetamine/aminoindane substitutions, could be worth looking into" before I replied. Wasn't intending to give offense, I thought this was a casual conversation.
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[*] posted on 27-2-2015 at 06:56


Quote: Originally posted by Etaoin Shrdlu  

You're right, my error, I was remembering something with a methylenedioxy ring. This book may be of some interest, perhaps.

While an excellent book to those in the field (I own it), it is worth pointing out that only passing mention is given to the title compounds (bromo and a methyl substitution as the R groups, taking liberties with the alkyl chain). The primary lit itself details more bio isosteric substitutions and a bit of the authors' colleagues' initial dispute on canonical ligand pose with regard to psychotropic effect (for which the constrained analog, not a new class, was helpful in elucidating before the advent of STD-NMR and X-ray crystallography). Without going through primary literature, you miss out on the reasoning and history of the 70s research. You also miss out on speculating on whether papers like Tet. Letters 66(2010)658-688 provide new conditions to the compounds similar to Tet. Letters 49(2008)6137-40.

The rat data for a QSAR extrapolation to humans is discussed in more detail elsewhere as well, but the key takeaways would be reduced, if any, potency with respect to the freely rotating analogs for the pharmacology, and poor reported initial yields for the chemistry. Combine the former with a lack of toxicological data, and you have the potential for greater propensities of off-target effects with no assurance of similar psychotropic activity given some of the data. Even then, discrimination between dysphoric compounds was not accomplished, so an abuser may find the entire thing unpleasant.

But to beat a dead horse, the lack of toxicological data is key. Anyone experienced in QSAR could take the homology of your targets, the affinity data from your model organism, extrapolate rankings to the human receptor, and if really inclined... Could cross compare CoMFA or DFT with various other receptors to try and get an idea of promiscuity for the target compound... And yet you would still have absolutely no idea how toxic these would be either acutely or chronically. There are hints that acute vasoconstriction and hypertension could be side effects, and knowledgeable people would be remiss not to speculate on behavioral toxicity and/or possible cardiac fibrosis as chronic risks. The latter are unmentioned anywhere I see, but likely taken as understood to anyone remotely interested in using these.
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[*] posted on 27-2-2015 at 16:47


Quote: Originally posted by Chemosynthesis  
Tet. Letters 66(2010)658-688

"Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate and subsequent site-selective Suzuki–Miyaura reactions"

Quote: Originally posted by Chemosynthesis  
Tet. Letters 49(2008)6137-40.

"1,4-Cyclohexadiene with Pd/C as a rapid, safe transfer hydrogenation system with microwave heating"

That's what I came up with looking through ScienceDirect's contents for Tetrahedron Letters. A glitch in their site maybe? Or are you getting at something very subtle? I don't see how these relate to pharmacology or indane though the last one looks like fun.

What I found interesting about the book was that it was a secondary reference mentioning interest in this "DOx-related" series, it referenced an established acronym for one, and touched on usage rates for 2-AI compounds. If this really were a great skeleton for recreational drugs I find the lack of bandwagoning on it strange.
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[*] posted on 27-2-2015 at 18:02


Quote: Originally posted by Etaoin Shrdlu  

"Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate and subsequent site-selective Suzuki–Miyaura reactions"

That looks more like Tetrahedron Letters
Volume 51, Issue 4, 27 January 2010, Pages 657–660
Quote:
"1,4-Cyclohexadiene with Pd/C as a rapid, safe transfer hydrogenation system with microwave heating"

There is an intermediate in there. That one was cited elsewhere, so I can't take credit for noticing.

Quote:

What I found interesting about the book was that it was a secondary reference mentioning interest in this "DOx-related" series, it referenced an established acronym for one, and touched on usage rates for 2-AI compounds. If this really were a great skeleton for recreational drugs I find the lack of bandwagoning on it strange.

The rigidity of the structure almost certainly prevents optimal binding conformation and efficacy. The rat data is out there and I'm not wasting computational cycles on checking on a human protein model. The real use was explained in primary literature as being able to hold the flexible amino group in a position analogous to nitrogens in LSD, and then modify various positions elsewhere on the molecule to see where hydrogen bonding is, or how altering electron density, or some sterics influences the drug interaction. Importantly, this doesn't tell anything definitively about promiscuity, toxicity, etc. Sometimes rough trends can be drawn from descriptors, but nothing definitive.

The timing of publications really gave away the receptor probe uses, as in essence, pharmacology of the 70s didn't have protein models like we do today, so rather than work from the receptor structure backwards towards novel drugs, the only real option was to painstakingly modify different ligands and check to see what bound with more or less affinity, and correlate these to the shape of a protein's active site.

Because the amphetamine structures have more conformational freedom and a higher point group than something constrained within a plane, like the aminoindoles, this leads to questions of what 3-dimensional position the molecule prefers energetically when bound to the receptor. By piecing together lots of individual descriptors such as molecular geometry, with efficacy data and binding affinity, you can try to understand what an active site looks like. It gets extremely nuanced.

But basically, yes, it looks like you'd be making a less potent psychedelic which may make it more dangerous depending on how promiscuous its binding profile. It may have zero psychotropic effect in humans, or it may have undesirable ones. The rat data is a bit conflicted.

I am blanking on the example I had earlier today (where agonism turned to inverse agonism depending on animal model), but off the top of my head chloroproxyfan has different agonism properties between rats/mice and humans, so there are any number of reasons this has yet to make it into recreational markets, and doesn't seem as though it is going to any time soon.
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[*] posted on 27-2-2015 at 18:21


Quote: Originally posted by Chemosynthesis  
Quote: Originally posted by Etaoin Shrdlu  

"Synthesis of 3,5-diaryl-4-chlorophthalates by [4+2] cycloaddition of 1-ethoxy-2-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene with dimethyl acetylenedicarboxylate and subsequent site-selective Suzuki–Miyaura reactions"

That looks more like Tetrahedron Letters
Volume 51, Issue 4, 27 January 2010, Pages 657–660

It is. Was 66 not a typo? That was the closest match I could find.

I know these were developed as receptor probes, not new-fangled drugs, I don't disbelieve you and have no reason to. If I'm coming off that way I apologize. Always interesting to hear about drug design from someone who is actually involved with it.

[Edited on 2-28-2015 by Etaoin Shrdlu]
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[*] posted on 27-2-2015 at 18:40


Quote: Originally posted by Etaoin Shrdlu  

It is. Was 66 not a typo? That was the closest match I could find.

If I were smart about it, i wouldn't have missed the issue number. I will check later to see if I can find it in that computer's history.

Quote:
I know these were developed as receptor probes, not new-fangled drugs, I don't disbelieve you and have no reason to. If I'm coming off that way I apologize. Always interesting to hear about drug design from someone who is actually involved with it.
You aren't coming across as that at all. I am just a little worried that research chemical vendors might read and get the wrong impression. I had read an article this week that seemed to imply the authors believed that Internet speculation on drugs forums actually influenced research chemical production. I get creeped out at the thought of someone assuming it is profitable and hiring some overseas lab to synthesize a bunch of it.
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[*] posted on 27-2-2015 at 19:05


Speculation does influence RC production, unfortunately, in "nootropics" at least I've watched it snowball. Fluorenol's the only one I remember offhand. Someone found a study (I think in rats) suggesting it was an active metabolite of modafinil responsible for wakefulness, bought some, and within months everyone and their dog was hawking it. People do what they do.
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[*] posted on 27-2-2015 at 19:16


Volume 66, Issue 3, 16 January 2010, Pages 685–688 was what I meant to cite originally.
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