I Like to Draw Pictures of Random Molecules

[crmt28]

How many of us have ever seen an Ar-O-CF3 (Ar-O-CH2CF3, yes) or an R-NF2?

Never seen it anywhere. I thought it would be a nearly impossible compound, but surprisingly the 2-(Trifluoromethoxy)benzaldehyde precursor seem to be widely available.

The NF2 bond was actually an accident! I wasn't expecting the perfluoro- prefix to fluroinate the amine.
But N,N-difluoromethanamine exists too!

Not sure if it can be used to synthesize N,N-difluorophenethylamine. I'm still studying a bit about reactions.

 

[Dresden]

Fluorine is the most electronegative element (with oxygen being a close second), but it is about the size of a hydrogen atom and thus not as an effective electronegative atom to add to a molecule as bromine or chlorine due to the "heavy atom effect." It's like your greatest impact on impacting the electronegativity of a molecule comes from an atom's innate electronegativity (which F is the winner of) times its atomic weight, and in this calculation, bromine and chlorine come ahead of fluorine. That's why you'll see Br or Cl on my structures far more often than F. They are simply more effective in influencing drug behavior because they influence the molecular orbital of the drug more than F does. And that's all I have to say about the matter other than it's a very common and sophomoric drug design mistake. To reiterate:

is probably going to be less of an impressive drug than

as far as entactogenesis goes because while F and Cl are both highly electronegative, the Cl is also bigger and heavier.
I hope that makes sense because I'm not explaining it again.

I really wasn't going to take the time to try to explain why the whole "Oh, F is the most electronegative element" and "electronegativity plays a huge role in drug design" (both of which are true statements) and coming to the conclusion "so I'll just stick a F on this drug here for maximum effect" (which is not true), but you seem earnest and clever so I did.

Even then, it's not as simple as drawing per-chloro (as opposed to per-fluoro) 2CC now and expecting anyone to take that seriously.

 

[crmt28]

I wasn't expecting anyone to take perfluoro-2C-C seriously! I was just joking around with chlorofluorocarbons and greenhouse gases

Fluorine being smaller is exactly my point! The methylthio group is already too big and seems to decrease activity on 2C-x compounds. (see BIS-TOM on PiHKAL)
Putting any other halogen in there would reduce activity in the same way.

The 5-EtO analogue is a little bit larger than MeO and this increases the duration 3-fold according to Shulgin!

I would expect a trifluoromethoxy version to be somewhere in between.

 

[aced126]

Fluorine is the most electronegative element (with oxygen being a close second), but it is about the size of a hydrogen atom and thus not as an effective electronegative atom to add to a molecule as bromine or chlorine due to the "heavy atom effect." It's like your greatest impact on impacting the electronegativity of a molecule comes from an atom's innate electronegativity (which F is the winner of) times its atomic weight, and in this calculation, bromine and chlorine come ahead of fluorine. That's why you'll see Br or Cl on my structures far more often than F. They are simply more effective in influencing drug behavior because they influence the molecular orbital of the drug more than F does. And that's all I have to say about the matter other than it's a very common and sophomoric drug design mistake. To reiterate:

is probably going to be less of an impressive drug than

as far as entactogenesis goes because while F and Cl are both highly electronegative, the Cl is also bigger and heavier.
I hope that makes sense because I'm not explaining it again.

I really wasn't going to take the time to try to explain why the whole "Oh, F is the most electronegative element" and "electronegativity plays a huge role in drug design" (both of which are true statements) and coming to the conclusion "so I'll just stick a F on this drug here for maximum effect" (which is not true), but you seem earnest and clever so I did.

Even then, it's not as simple as drawing per-chloro (as opposed to per-fluoro) 2CC now and expecting anyone to take that seriously.

True, and you're correct in the instance of ring substituted amphetamines, however as you said since chlorines and bromines are big, they could sterically hinder the molecule from binding to the target, and in that case a fluorine which wouldn't cause this yet still increasing affinity would be a better option. Also substituted halogens on rings block enzymatic hydroxylation where they're substituted as well as other ring positions due to its electron withdrawing effects on the ring.

This molecule might've already been drawn, but I'll explain my rationale behind it.

TFM group on amine likely reduces its basicity which will decrease potency (amine charged when interacting with its targets most likely). However the molecule will be more lipophilic which could make up for lost potency. However I think it might actually have a shorter half life than meth. I suspect trifluoromethylamine (a weaker base due to the fluorines reducing the nitrogen lone pair's nucleophilic power) is a better leaving group than methylamine itself, and thus deamination would occur quicker. Anyone who knows about deamination and these kinds of metabolic reactions in detail can correct me.

 

[aced126]

Well, these structures are based on morphine, and morphine has a 6-OH but a 6-oxo or a 6-acetoxy can be derived from the hydroxy, and both make the entire molecule get into the brain much better than if morphine's 6-OH was just left there. Since these two molecules would likely be made from scratch, I guess you're right though. I was kind of always under the impression that they were necessary for activity or helped it somehow, but hey, my specialty is the amphetamines, not the opiates. Amphetamines are delightful and amenable to so many structural changes.

I get you, the acetoxy would be added because it is easier to do so to morphine rather than remove the 6 hydroxy group completely and make it saturated. This would indeed increase logP without affecting potency. In fact, I believe aliphatic chains on carbon 6 of morphine yields potent derivatives (think adder mentioned this). So yeah, the 6 position doesn't seem to play a big role in actual receptor interactions but rather just lipophilicity of the molecule.

 

[adder]

In fact, I believe aliphatic chains on carbon 6 of morphine yields potent derivatives (think adder mentioned this). So yeah, the 6 position doesn't seem to play a big role in actual receptor interactions but rather just lipophilicity of the molecule.

It's not necessarily just about lipophilicity. In case of plain alkyl/alkoxy chains it might be true, take heterocodeine as an example, its potency doesn't correlate well with its affinity vs. morphine, but if you start putting longer alkyl chains there with heteroatoms at the end of the chain, then they actually do take part in binding (interaction with K233). There are quite a few irreversible MOP ligands that make use of it (chlornaltrexamine, beta-funaltrexamine etc.), strong binding of chloromorphide is likely due to chlorine interacting with K233 as well. However, there might also be a possibility to direct the C6 alkyl/alkoxy substituent into the region which bulky C7-substituents of orvinols bind to, it's just a matter of getting the C ring to take the right conformation.

 

[Nagelfar]

The above PTs that are meta-cis-propenyl have great SERT & DAT but low NET affinity; *all of them*, for instance the middle one's Ki for SERT is 0.05, DAT 3.45 and NET is 24

now the para-cis-propenyl of troparil is even better:

SERT= 7.1
DAT=15
NET=28,000(!!!)

So I take the amphetamine skeleton from the phenyltropane; beingthe line along the string of bonds on the top of the PT from the benzene, and wonder if, then, as a VMAT substrate releasing agent, the para-cis-propenyl'd do the same for negating norepinephrine affinity for it as it does for the DRI; since it lengthens the molecule taking off the n-methylated part and presume SERT affinity stays as good as methamp but without the NE release:

para-cis-propenyl-amphetamine, a winner? (since PCP-amphetamine would just confuse people, call it Parcip-amphetamine, since it's close to the German for Percival "Parzifal", Percival can be it's street name; the "holy grail of stims" ;-p )

taking this above example of "epibati" tropane, and thinking of the way in which desoxypipridrol binds in 360 degree rotation, and how the nitrogen works with the cycloalkane, I come up with this:

What'd you all think the benzene relation would be^ might it work with the cycloalkane being changed to a straight benzene perhaps? Triple phenyl with nitrogens a DRI?

 

[Nagelfar]

Strobamine plus + SoRI-20041 equals =

dopamine transporter allosteric modulators are the future of stimulants, IMHO

 

[neurotic]

Serotonin/dopamine selective stimulants... Now that's interesting. I'd love to try. These compounds have never tried by anyone I guess? Neither human not mouse?

Just a thought though: even though noradrenaline is like the shitty monoamine, I'd bet that it is necessary, to some degree, for the stimulant effects as we know them, that is, 5HT/DA selective stimulants might not be better perhaps just different or even uninteresting. Ofc just speculation.

 

[Nagelfar]

Serotonin/dopamine selective stimulants... Now that's interesting. I'd love to try. These compounds have never tried by anyone I guess? Neither human not mouse?

http://pubs.acs.org/doi/abs/10.1021/jm060641q "In vivo study: rat, mouse, monkey & non-human primate"

So apparently, those top meta-substituted ones have been tried in invivo in animals, I don't see why'd they bother radiolabling them if that were not the case: also check out:
https://en.wikipedia.org/wiki/RTI-83

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841478/ "Development of 3-Phenyltropane Analogs with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter"

 

[Nagelfar]

What'd you all think the benzene relation would be^ might it work with the cycloalkane being changed to a straight benzene perhaps? Triple phenyl with nitrogens a DRI?

Holy heck, here is exactly what I was talking about there.

Apparently it is quite the stimulant.

EDIT:

Throw in some more heteroatoms, and since most can visualize that, I'm mixing in the Hexapradol tail, but using the phenmetrazine of the desoxypipridrol (i.e. 3-Benzhydrylmorpholine) but giving it a benzene and a nitrogen to emulate the fentanyl skeleton, 'cause that back when still intrigues me:

Put on the naphthyls on a whim, too

 

[roi]

 

[crmt28]

2C-T-21/2C-EF analogue. 2C-EP!

Roi, about your first molecule, I was thinking of this instead, since the methoxy groups would be closer to the 2,5 positions:

 

[SKL]

Serotonin/dopamine selective stimulants...

Isn't 4-MAR one? Or at least overwhelmingly favoring S/D?

*persevering about 4-MAR

 

[neurotic]

i found this paper here - https://bitnest.netfirms.com/external.php?id=%7DbxUgXXCNAUj%7By%02%0D, check out pages 9 & 10

tested three aminorex analogues and d-amphetamine for monoamine release, "All test drugs were fully efficacious in their ability to evoke release at DAT, NET and SERT, i.e. drug effects achieved 100% of maximal release.". the aminorex's look like they are awesome stimulants btw.

 

[Nagelfar]

i found this paper here - https://bitnest.netfirms.com/external.php?id=%7DbxUgXXCNAUj%7By%02%0D, check out pages 9 & 10

tested three aminorex analogues and d-amphetamine for monoamine release, "All test drugs were fully efficacious in their ability to evoke release at DAT, NET and SERT, i.e. drug effects achieved 100% of maximal release.". the aminorex's look like they are awesome stimulants btw.

Anybody find anyone ever synthing that para-propenyl-amp, ever, at all...? I think that should be rushed to right away as top priority if not, anyone reading this? ;-p

Alpha-methylated tryptamines are indeed mostly unpromising. Maybe the beta position would be a better choice?

3-(2-morpholinyl)-indole

It actually already exists and even has a CAS number. But absolutely no papers explaining what it does. Interesting!

Is it just me, or does the pyrrole on the indole make one of those optical illusions that makes tbe morpholine looks one bond bigger than the benzene? I think the optical illusion has something to do with the benzene having the border lining the inner pi-orbital bonds; 'cause I think I've seen that on an optical illusion website "which box is bigger" when they're exactly the same circumference but everyones eye is trained to deceive you otherwise

 

[aced126]

Anybody find anyone ever synthing that para-propenyl-amp, ever, at all...? I think that should be rushed to right away as top priority if not, anyone reading this? ;-p

Yeah it'd be good if it was synthesised and evaluated but amps mechanism of action is different to phenyltropanes which are reuptake inhibitors, not releasing agents, so I don't think you can fully apply the same logic to amps.

 

[aced126]

I know that barely information is available regarding the 5-HT2b SAR, but I was wondering if the design of a possible charged 2b antagonist which doesn't cross the BBB could be done? This could mean that the 2b therapeutic target could be opened up again, and that drugs like fenfluramine, aminorex and MDMA wouldn't have that issue of cardiac fibrosis.

This probably won't result in antagonism but everyone gets the point.

Opsin doesn't allow more than 3 bonds to nitrogen so just imagine there's another methyl on the nitrogen so it can't cross the BBB. Yeah, the 2b receptor probably is quite different to opioid receptors but at least its a start.

 

[Nagelfar]

Yeah it'd be good if it was synthesised and evaluated but amps mechanism of action is different to phenyltropanes which are reuptake inhibitors, not releasing agents, so I don't think you can fully apply the same logic to amps.

I understand that of course, but the underlying basic shape along the top is the same ligand structure, the larger "below the boat - iceberg" of the PTs are what keep them from going all the way up intothe pump, and anchoring on to just be a reuptake inhibitor.

 

[aced126]

I understand that of course, but the underlying basic shape along the top is the same ligand structure, the larger "below the boat - iceberg" of the PTs are what keep them from going all the way up intothe pump, and anchoring on to just be a reuptake inhibitor.

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.