I Like to Draw Pictures of Random Molecules

[Nagelfar]

I thought it wasn't only due to sterics and the carboxyl played a role electronically to hold it to the transporter.

clubcard has gone over this numerous times just recently, the carboxyl isn't necessary, and infact just disables the ability to bind as a ligand in full if it is just a "carboxyl" and not a "carbmethoxy"

para-FBT is a fully functional and efficacious DAT uptake pump ligand:

tropacocaine is roughly one 58th the potency of cocaine (at inhibiting the phenyltropane "CFT" from binding to just DAT, so not a definite scale of potency in over-all terms), it has no 2-tropane branch whatsoever, but benzoylecgonine (just a carboxyl, no methyl on it) is roughly 2,191th the strength, less than one two-thousandth cocaine's inclination to displace CFT from the DAT reuptake site, which is essentially saying no affinity at all, probably has the same measure of affinity for the opioid receptor (the fact that the molecule floats around the body indiscriminately makes pretty much any site measurable for any compound, and such a number is a way of saying "not a ligand")

 

[aced126]

clubcard has gone over this numerous times just recently, the carboxyl isn't necessary, and infact just disables the ability to bind as a ligand in full if it is just a "carboxyl" and not a "carbmethoxy"

tropacocaine is roughly one 58th the potency of cocaine (at inhibiting the phenyltropane "CFT" from binding to just DAT, so not a definite scale of potency in over-all terms), it has no 2-tropane branch whatsoever, but benzoylecgonine (just a carboxyl, no methyl on it) is roughly 2,191th the strength, less than one two-thousandth cocaine's inclination to displace CFT from the DAT reuptake site, which is essentially saying no affinity at all, probably has the same measure of affinity for the opioid receptor (the fact that the molecule floats around the body indiscriminately makes pretty much any site measurable for any compound, and such a number is a way of saying "not a ligand")

Ahh I see, I meant carbmethoxy, sorry. Would a molecule like this be transported into the neuron or simply block the transporter?

Looks very amphetamine like

 

[Dresden]

I know troparil

was a huge disappointment. Not sure about your 3-phenyltropane

But hey, it looks great on paper.

Maybe add an electron withdrawing 3,4-methylenedioxy group?

 

[aced126]

Maybe add an electron withdrawing 3,4-methylenedioxy group?

Wouldn't the electron donating resonance outweigh the inductive withdrawing effects of the oxygens and increase the electron density of the ring?

So if carbmethoxy plays no role in actually holding the molecule to the transporter what does it actually do then? I think I might've already posted this molecule before but I'll do it again. I don't know why no researchers have made this and found out how it works.

If that molecule shows reuptake abilities only then we know the carbmethoxy is binding to something on the transporter. However ...

If this shows reuptake abilities only then it would suggest the carbmethoxy group doesn't really do anything, although I suspect this molecule will be act like a normal substrate at DAT and dissociate from the transporter once in the presynaptic membrane, and then go on to release DA through normal amphetamine action.

 

[Dresden]

Wouldn't the electron donating resonance outweigh the inductive withdrawing effects of the oxygens and increase the electron density of the ring?

1. Yes, you're right. Otherwise oxygenated arenes wouldn't be ortho/para directing.

2. As for the carbomethoxy issue, all I know is that esters are fruity and usually smell delicious, which could possibly make them more desirable when incorporated into drugs of abuse.

3. As for

Idk again, but I've heard that it is one of the worst drug experiences imaginable.

But speaking of such possibly hellish ideas (since Halloween is Saturday), raspberry ketone is a widely available, cheap, unwatched compound:

Raspberry Ketone (found in red raspberries)

Which could lead to this:

First sassafras, now raspberries!!!

Finally,

alpha-methylfluoxetine (alpha-methyl-Prozac; AMProzac)

 

[Dresden]

These are my antibiotics. This is my prior art.

2-carbomethoxy penicillin G; intended to get into the brain much better than plain penicillin G (which is identical but has a 2-carboxylic acid) when administered intravenously; for use in neurosyphilis (which only has a cure rate of 50% at the moment with the current pen G regimen) and other brain infections.

This one is identical to the above one, but with inspiration from chloramphenicol; for IV use. For the treatment of bacterial meningitis and neuro/syphilis and other susceptible infections of the brain.

The methoxylation of the carboxylic acid to the carbomethoxy group can be applied to any penicillin or cephalosporin antibiotic used to treat brain infections.

The last one is for oral use and is intended for the treatment of acne vulgaris, (non-neuro)syphilis, and probably many other infections.

If you know anyone in the big pharma business, please show them this post.

 

[aced126]

Good idea...but surely they would've made and tested alkyl esters?

 

[Dresden]

It may depend on which was discovered first: most penicillin/cephalosporin antibiotics or the blood brain barrier? To me, the bigger question is why wouldn't these carbomethoxy pro drugs work when given IV as superior brain permeating drugs? After all, we know that the brain contains esterases. Either way, though, the last one is still a 2-carboxylic acid. And here's chloramphenicol's structure for easy reference:

The dichloroacetate is metabolized away IIRC. Chloramphenicol is a natural product.

Then there's this (and the 2-CO2H analogue), which may be a stretch due to possible unwanted CNS stimulation:

And this one (and its 2-CO2H analogue), which actually looks rather promising...

A molecule can have up to two bare hydroxyls and still manage to make it into the brain well enough.

 

[Nagelfar]

Ahh I see, I meant carbmethoxy, sorry. Would a molecule like this be transported into the neuron or simply block the transporter?

Looks very amphetamine like

It is, the following is a DA releaser rather than a DAT re-uptake pump ligand:

http://www.bluelight.ru/vb/showpost.php?p=5728429&postcount=10

and check out:

exo-2-Phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic Acid: A New Constrained Proline Analogue.

 

[Dresden]

I wouldn't mind trying that.

And this:

And this:

Nifty!

 

[aced126]

It is, the following is a DA releaser rather than a DAT re-uptake pump ligand:

If this is the case then surely it is likely that the molecule I drew would display similar amphetaminergic releasing qualities. Surely then the addition of the carbmethoxy group will prevent it from dissociating with the receptor once presynpatic membrane bound (or dissociating to a lesser extent at least) and thus the molecule is an inhibitor rather than releaser.

 

[aced126]

It may depend on which was discovered first: most penicillin/cephalosporin antibiotics or the blood brain barrier? To me, the bigger question is why wouldn't these carbomethoxy pro drugs work when given IV as superior brain permeating drugs? After all, we know that the brain contains esterases. Either way, though, the last one is still a 2-carboxylic acid. And here's chloramphenicol's structure for easy reference:

The dichloroacetate is metabolized away IIRC. Chloramphenicol is a natural product.

Then there's this (and the 2-CO2H analogue), which may be a stretch due to possible unwanted CNS stimulation:

And this one (and its 2-CO2H analogue), which actually looks rather promising...

A molecule can have up to two bare hydroxyls and still manage to make it into the brain well enough.

Doesn't most of the ester hydrolysis process happen in the liver? You don't see much ritalinic acid or benzoylecgonine being made in the brain itself. So I'd imagine an absurd dose would be needed if the intention is to hydrolyse the molecule once past the BBB. Nevertheless the methylester could be efficacious itself, but I know nothing about antibiotic SAR and couldn't possibly comment.

In the last molecule in particular, wouldn't the increased logP due to the methylester be outweighed by the several other polar FGs in the molecule, like the p-nitro especially. Although admittedly if you had to put one substitution in to increase logP the most it would probably be esterification.

Edit: My bad, it seems nitro groups don't seem to alter logP a lot on rings. The calculated logP for the carboxylate was 1.5 and for the carbmethoxy was over 3, so yeah that molecule is probably gonna cross into the brain pretty well.

 

[Dresden]

You know, like IV heroin (diacetylmorphine) gets into the brain 3x better than morphine when IV'ed because it is more lipophilic. As for your molecule, it doesn't have the same "amphetamine spacing" as Nagelfar's. Of course, that doesn't mean it's not active as well.

 

[adder]

I thought it wasn't only due to sterics and the carboxyl played a role electronically to hold it to the transporter.

Edit: I meant carbmethoxy.

The fact that it isn't necessary doesn't mean it's not playing a role in binding if it's there. I suppose it dramatically increases affinity. From what I've seen the carbomethoxy in phenyltropanes binds to the same tyrosine residue that phenyl in amphetamine does. I suppose the aromatic hydroxyl is crucial here impacting the aromatic ring electronically in such a way that an ester can bind. If you look at more sophisticated phenyltropanes, you can see that many different groups bioisosteric with carbomethoxy, like aromatic isoxazolyl, were tried and seem to do well.

 

[aced126]

If this is so then what does the phenyl in phenyltropanes do? So the reason why amphetamine dissociates from DAT once inside the neuron is because the interactions between the amph pi cloud and the tyrosine pi cloud are weak? But the carbomethoxy (or bioisostere) has strong enough binding to the tyrosine pi cloud/hydroxyl itself to prevent dissociation once exposed to the presynaptic membrane? Or maybe the carbomethoxy binding instead of the phenyl means the phenyl can interfere in the conformational change the transporter undergoes when in the process of transportation of substrate from synaptic cleft to cytosol?

 

[Dresden]

If the carbomethoxy binds to the same site as the phenyl, then wouldn't this

do something good?

 

[aced126]

That's what I had in mind. Seems like that would have many other targets in the brain though and might not be selective enough. LogP seems fine for that compound as well though. Ahh, if the phenyl ring in phenyltropanes interferes with the conformational change process, and nothing is there to do that on this molecule, it might dissociate once in the presynaptic membrane. How is it then supposed to release dopamine? It might release vesicular DA via altering the proton gradient (I think only a basic nitrogen is needed for this) but how is it supposed to reverse the function of DAT? It might not bind properly to TAAR1 which is needed for DAT reversal I believe.

 

[aced126]

On a different topic, which of the lone pairs in iso-oxazole is donated into the ring? One of the 2 oxygen lone pairs or the nitrogen lone pair?

 

[Dresden]

And of course the 4-OH and 5-MeO analogues.

What would result if methamphetamine and Strattera had a baby.

 

[Dresden]

On a different topic, which of the lone pairs in iso-oxazole is donated into the ring? One of the 2 oxygen lone pairs or the nitrogen lone pair?

How do you expect anyone to know that answer?