eleusis-borodin
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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.
E. Borodin
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Chemosynthesis
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Are you interested in the synthesis or how well the compound would fit into the pharmacophore model, QSAR estimates, etc.?
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Etaoin Shrdlu
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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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Chemosynthesis
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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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eleusis-borodin
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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.
-E. Borodin
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eleusis-borodin
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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.
-E. Borodin
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Chemosynthesis
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| 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
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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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Etaoin Shrdlu
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| 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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Chemosynthesis
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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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Etaoin Shrdlu
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"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"
"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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Chemosynthesis
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| 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"
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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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Etaoin Shrdlu
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| 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"
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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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Chemosynthesis
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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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Etaoin Shrdlu
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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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Chemosynthesis
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Volume 66, Issue 3, 16 January 2010, Pages 685–688 was what I meant to cite originally.
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