I Like to Draw Pictures of Random Molecules

[SeenSoFar]

No, I mean in 3D. The 3D structure is what counts for binding. You can have things that look quite similar in 2D but that has a very dissimilar 3D structure. This, in the other hand, overlays with the fentanyl analogues that have a tertiary carbon on the piperidine ring almost exactly. Obviously the extra ring changes things a bit but not by much, everything ends up in the right place for good activity as far as I can see. Obviously it would have to be assayed to know for sure, but I would bet money on it being active.

 

[ebola?]

heading into overly philosophical territory:

if we think about it, all of these models are abstractions which obscure various aspects of chemical interactions, none really "reflecting nature". At root, these molecules are emergent patterns of multiple wave functions set in mutual relation, describing electron clouds' propensity to manifest as particle interactions which induce emerging aggregate entities with intelligible qualities as a whole (eg, as compounds, ions locked in interaction, polymers contorted due to emergent patterns of folding (eg, proteins), etc.) (and even this mathematized formulation abstracts from the place of observation in this process). But engaging the raw, non-composite phenomena involved tends to require unwieldily complex mathematics, but is also cast in terms unclear, ambiguous entities alien to those of the everyday; put bluntly, whatever one's imagined conception of wave-particles set in interaction, it will prove incomplete and misleading, even incoherent.

So to make things tractable, we pile on simplifying axioms that might reveal certain characteristics of interaction, as the computation required to literally model everything involved, as interacting electrons and more rarely nucleons, causally bound in a complex way, escalate too drastically with modest numbers of particles, even under limitations of sensibly coarse discretization of space and time. Worse still, continuous modeling is mathematically intractable in principle (see the 3 body problem).

So even a 3D space-filling model of ligand-active site docking will contain these distorting abstractions and computational frameworks (but very useful distortions in terms of highlighting hydrogen bonding, Van Der Waals forces, etc.) But if reality could be modeled trivially, would we actually gain anything from modeling it?

ebola

 

[sekio]

3d space filling models are pretty accurate as far as things go, w.r.t. their proof by NMR, X-ray diffraction, and the like.

 

[ebola?]

Right, but again, confirmation is cast in terms the way our instruments (of manipulation and observation) structure what can be manipulated and which aspects of the results of this manipulation will manifest as visible and intelligible; indeed, as a complex, the experimental and theoretical apparatuses play a key role in structuring what aspects of a fluid, ambiguous, flux before us we pull out as intelligible (but this flux does even more in structuring what aspects of it can appear as intelligible). . .

Now, I'm not saying the models are "bullshit" or even "false"...as we use corresponding tools to navigate and manipulate the world for us, we in turn change the world 'as such' (but in ways we don't understand), fashioning a world in our image (but also entailing novel, emergent dynamics to follow).

ebola

 

[sekio]

We can do some pretty amazing stuff with atomic force microscopy (like looking at reaction products before and after, like tiny ball and stick models), if that counts for anything.

 

[adder]

Wouldn't the potency of this "RC" be higher than Flunitrazepam because of the steric hindrance of the chlorinated benzene?

I know the methylamino group makes this RC more "fun" than Clonazepam.

Not sure if this fits in this forum or BDD. Sorry mods.

EDIT: APPARENTLY MY PHOTOBUCKET PICTURE WON'T LOAD, but the point still stands. Imagine the image in your head I suppose.

I did my best to imagine what I thought was obvious, but honestly I doubt that anyone could have guessed what you had in mind.:D Look up the structural formulas of flunitrazepam and clonazepam, because these have very little to do with them, one is completely wrong with the nitrogen at position 4. lacking one bond and the other one isn't even a benzodiazepine.

 

[Cone]

I did my best to imagine what I thought was obvious, but honestly I doubt that anyone could have guessed what you had in mind.:D Look up the structural formulas of flunitrazepam and clonazepam, because these have very little to do with them, one is completely wrong with the nitrogen at position 4. lacking one bond and the other one isn't even a benzodiazepine.

I got lazy when drawing and didnt double check my work. I didn't think it'd be a problem since its basically chlorinated flunitrazepam. Clonitrazepam would be a good name, no?

I'm actually more interested how halogens substituted at this position affect the potency, onset, and mechanism of action of a benzo (hypnotic, anxiolytic, onset, etc.)

 

[adder]

I'm confused now what compound you really mean. Is it flunitrazepam with the fluorine atom substituted with a chlorine atom? If yes, then the compound in question is "clonitrazepam", there's no better name actually for such a compound, I guess. In your image you have a chlorine atom on the 7th position while flunitrazepam and clonazepam have nitro groups there and that confused me.

I don't know much about different halogens effects at C2'. You would have to group benzodiazepines according to their substituents at the nitrogen, C3, C7, and C2', then look at their affinities at different GABA(A) subunits, and eventually draw conclusions. Here's a thread in which various subunits are listed with benzodiazepines binding to them, however it's not specific enough to draw precise conclusions. One thing you can notice though is that BZDs with 2'-fluoro all have high affinity towards alpha-1, which is related to amnesia and ataxia.

Fluorine at C2' will also be the best for a fast onset of action, it should attract the hydrogen atom from the neighbouring carbon atom from the aromatic ring making a molecule more lipophilic. It could be that it's there for the electronic effect on the phenyl ring, I've read an abstract stating that the 2',6'-difluoro analogue of diazepam is a potent compound, and 6'-fluoro increases the electronic effect of 2'-fluoro. Steric effect likely plays a role too, a chlorine atom is much bigger, and clonazepam is a bit more potent than flunitrazepam, which on the other hand could be attributable to higher affinity at some subunit due to a secondary amine rather than a tertiary amine. Honestly speaking, analysing stuff like this inevitably ends with some questions that can't be answered if you don't know to what residues of receptors a compound binds to, unless there are groups of compounds with different structure binding to the same receptors and it's possible to notice some analogies.

 

[SkyblueMolly]

This is a modified molecule of nomifensine. I call it fensine! It should be just like NZT without side effects, or like nomifensine without the blood cell destroying properties.

Here's another one. Cheryfensine.

Here's another one. Maybe this one is NZT. Norzatrensine.

Xenoninsinol.

Indofensine

This one is nomifensine. It already exist, but is here for reference purposes.

 

[DL-ark]

Is it possible that the nitrogen on the indole in tryptamines binds to the same spot in 5HT2A as the nitrogen in phenethylamines?

This would explain why N dimethylation among other things doesnt work with phenethylamines.

 

[sekio]

Nope... the N on PEAs hits a much different site than the indole N. I think I remember reading it has to do with the pH of the amine.

This would explain why N dimethylation among other things doesnt work with phenethylamines.

Even just N-methylation pretty much chops activity down by a large factor, and indole N is already secondary. Hence why you don't see more "N methyl 2C-D" etc.

This is a modified molecule of nomifensine. I call it fensine! It should be just like NZT without side effects, or like nomifensine without the blood cell destroying properties.

You'd like this paper. "Fensine" & its cousins are NDRI drugs... so they will unfortunately be expected to have the usual cocktail of NDRI side effects

 

[sekio]

"Ethoxetamine"... I guess

 

[DL-ark]

Nope... the N on PEAs hits a much different site than the indole N. I think I remember reading it has to do with the pH of the amine.



Even just N-methylation pretty much chops activity down by a large factor, and indole N is already secondary. Hence why you don't see more "N methyl 2C-D" etc.

Well, maybe not N-Methyl, but N benzyl... Think about how the N in the indole is bonded on the phenyl, so maybe the phenyl is equivalent to the n-benzyl on phenethylamines?

Still a long shot, but idk.

 

[LordJewington]

methyl N,N-dimethyl-tryptophan ester
This looks like it would probably be psychoactive and easy to synthesize. Thoughts?

 

[DL-ark]

methyl N,N-dimethyl-tryptophan ester
This looks like it would probably be psychoactive and easy to synthesize. Thoughts?

I think puting an methyl ester on the alpha position is going to cause some problems. it is pretty big and unweildy, and with likely metabolize to N,N dimethyl tryptophan which as far as I know, is inactive. Although, I have posted on here suggesting that alpha carboxylation of DMT could result in it being decarboxylating via aromatic amino acid decarboxylase, and serving as a prodrug for DMT. It would then be able to be taken orally without problems, and would have a longer effect.

 

[LordJewington]

I think puting an methyl ester on the alpha position is going to cause some problems. it is pretty big and unweildy, and with likely metabolize to N,N dimethyl tryptophan which as far as I know, is inactive. Although, I have posted on here suggesting that alpha carboxylation of DMT could result in it being decarboxylating via aromatic amino acid decarboxylase, and serving as a prodrug for DMT. It would then be able to be taken orally without problems, and would have a longer effect.

Shulgin addressed essentially the same idea here: http://www.cognitiveliberty.org/shulgin/adsarchive/dmt.htm

N-methylated tryptophan would not make it into the brain, which is where most aromatic-L-amino-acid decarboxalase is expressed. Its also doubtful that n-methylated tryptophan would be a suitable substrate for the enzyme.

Getting it past the BBB is why I thought of esterfying it (also because the compound could be made in two simple steps from tryptophan.) As you correctly point out, however, the ester bond would be unlikely to survive first-pass metabolism, and so the compound is unlikely to be orally active. However, taken intravenously I think enough of it would make it past the blood-brain barrier before the liver got a hold of it. You could also try covering up the carboxylic acid with an amide:

That's getting a little bit more synthetically complicated, but it might well be orally active and software predicts that it would be a strong GPCR ligand.

Alpha substituted tryptamines haven't been explored very much, as far as I can tell. The only ones that I know of have had either a simple methyl or ethyl in the alpha position. So, the SAR doesn't seem to be known well enough to say what a methyl ester in the alpha position would do to the activity.

 

[DL-ark]

Shulgin addressed essentially the same idea here: http://www.cognitiveliberty.org/shulgin/adsarchive/dmt.htm

N-methylated tryptophan would not make it into the brain, which is where most aromatic-L-amino-acid decarboxalase is expressed. Its also doubtful that n-methylated tryptophan would be a suitable substrate for the enzyme.

Getting it past the BBB is why I thought of esterfying it (also because the compound could be made in two simple steps from tryptophan.) As you correctly point out, however, the ester bond would be unlikely to survive first-pass metabolism, and so the compound is unlikely to be orally active. However, taken intravenously I think enough of it would make it past the blood-brain barrier before the liver got a hold of it. You could also try covering up the carboxylic acid with an amide:

That's getting a little bit more synthetically complicated, but it might well be orally active and software predicts that it would be a strong GPCR ligand.

Alpha substituted tryptamines haven't been explored very much, as far as I can tell. The only ones that I know of have had either a simple methyl or ethyl in the alpha position. So, the SAR doesn't seem to be known well enough to say what a methyl ester in the alpha position would do to the activity.

Has shulgin adressed something like alpha-carboxylated MDPEA/MDA? Or an alpha carboxylated 2c? oh man an alpha-carboxyl 2c-e could be a very good alternative for getting around the law....

 

[sekio]

from what I recall, "tryptamino acids" are not promising drug candidates due to their metabolic lability & higher polarity than equivalent alkylated tryptamines/PEAs.

 

[LordJewington]

from what I recall, "tryptamino acids" are not promising drug candidates due to their metabolic lability & higher polarity than equivalent alkylated tryptamines/PEAs.

Once you cover up the carboxylic acid group with something, polarity becomes much less of an issue. The predicted octanol/water partition coefficient logP for methyl N,N-dimethyl-tryptophan ester is 2.146 vs 2.297 for DMT. Total polar surface area is 45.334 which is high compared to DMT's 19.029, but caffeine makes it across the BBB with a TPSA of 61.836. (all figures calculated using molinspiration)

I'm fairly confident that if taken intravenously, the ester would make it into the brain with no problem. The real question is what would happen once it gets there considering that alpha substituted tryptamines haven't been explored very much

 

[sekio]

the problem is the ester often doesn't stay there... aren't they susceptible to carboxylesterases (e.g. serum butyrylcholinesterase) though? i know chymotrypsin would bust the esters up in the gut. esters are more susceptible to hydrolysis than amides, iirc.

it really would not be that difficult to test in vivo the activity of e.g. tryptophan methylester. it would probably take some thought and care to methylate it selectively w/o doing a pictet spengler though.

... apparently people have tested direct brain injections of a few amino acid methyl esters into rats (DL-p-chlorophenylalanine, L-lysine, L-tryptophan) and noted that they "increase food consumption" through a "non serotonergic effect".

And another curious paper: The Major Alkaloid of Pultenaea altissima F. Muell. ex Benth., N,N,-Dimethyl-L-tryptophan Methyl Ester. So it's naturally occuring.