I Like to Draw Pictures of Random Molecules

[Nagelfar]

Actually you'll be surprised that the energy minimized conformation of 3C-PEP overlay with that of methylphenidate..

Really? Do you (or does anybody for that matter whose willing?) have a 3D molecular drawing program that could overlay those two for me? I'd be very interested to see it, even to have to released and uploaded on Wikimedia commons for Wikipedia; I already have methylphenidate overlays as the litmus test for typical monoamine reuptake inhibitors. As for German; "N ohne Radikal" ;-P

 

[Dresden]

I'm sure this one was checked out long ago, but then again, I don't know that.

 

[MrPorter]

I'm really interested in the naphthyl-PT substitutions: Can't wait until I get this beyond just its abstract, I'm going to have a heyday:

Synthesis of 2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and Their Binding Affinities at Dopamine and Serotonin Transport Sites

I have full access. How's best to upload?

 

[Nagelfar]

I have full access. How's best to upload?

I do too now. No worries, even have a hard copy at home. Didn't notice they were acyl @ 1st, and sadly, the substituents on the aryl do not seem to potentiate.

 

[DotChem]

Really? Do you (or does anybody for that matter whose willing?) have a 3D molecular drawing program that could overlay those two for me? I'd be very interested to see it, even to have to released and uploaded on Wikimedia commons for Wikipedia; I already have methylphenidate overlays as the litmus test for typical monoamine reuptake inhibitors. As for German; "N ohne Radikal" ;-P

Now that I manage to have some time on my hand: [MENTION=99760]Nagelfar[/MENTION]: here is 3D model so you can see I was talking about re: 3C-PEP conformation is actually closer to that of methylphenidate:

Blue is MPH the light green is PEA-piperazine (compound to the right)

I use the 1-phenethylpiperazine to show you that the phenethyl of 3C-PEP overlay with that of MPH and the piperazine overlay with the piperidine of MPH. I use the PEA-piperazine instead of the PEA phenylpiperazine because the basic 3- point pharmacophores of MPH is there in 3C-PEP (more or less as there is room to fit the bigger phenylpierazine). Actually bigger may be better than the piperidine of MPH. But anyhow, you get the idea..( you can try it yourself with various PEA piperazines substituted at N4: Chemaxon Inc they use to have freeware for conformational analysis and such..I don't know if it still free.. but any decent library should have subscription!


PS: note the 1-Phenylethylpiperazine is actually a potent MAT inhibitor with more serotonergic though.. so most likely will be like MDMA or BZP..but who knows? unless somebody actually try it! (will get post references later)

 

[Nagelfar]

Now that I manage to have some time on my hand: [MENTION=99760]Nagelfar[/MENTION]: here is 3D model so you can see I was talking about re: 3C-PEP conformation is actually closer to that of methylphenidate:

Blue is MPH the light green is PEA-piperazine (compound to the right)

I use the 1-phenethylpiperazine to show you that the phenethyl of 3C-PEP overlay with that of MPH and the piperazine overlay with the piperidine of MPH. I use the PEA-piperazine instead of the PEA phenylpiperazine because the basic 3- point pharmacophores of MPH is there in 3C-PEP (more or less as there is room to fit the bigger phenylpierazine). Actually bigger may be better than the piperidine of MPH. But anyhow, you get the idea..( you can try it yourself with various PEA piperazines substituted at N4: Chemaxon Inc they use to have freeware for conformational analysis and such..I don't know if it still free.. but any decent library should have subscription!


PS: note the 1-Phenylethylpiperazine is actually a potent MAT inhibitor with more serotonergic though.. so most likely will be like MDMA or BZP..but who knows? unless somebody actually try it! (will get post references later)

I guess the reason I found it odd, overlaying with MPH while still being a DARI of that pharmacophore, is that bulky para substituents either on the benzene or the cyclohexane on the other side (see fentanyl) like another phenyl (bi-phenyl) greatly diminish MPH activity. But barring that specific 3-chlorophenyl, if that's (as you mean) 1-(2-Phenylethyl)piperazine that is a reuptake inhibitor, what about 1-(1-Phenylethyl)piperazine? The former reminds me of cyclomethiodrone/TCAT and similar.

What I find equally baffling, though, is:

and benzyl tropanes have good activity e.g.

but...benzyl analogues of MPH i.e.

have >5,000 Ki inhibition @ DAT

...I suppose the angle if those two specific compounds were overlayed might be off (humor me again? can't download programs on the library computer which is my sole online access), but still I would imagine to overlay in some rotations / conformations

Could I crop your name out of that overly and make it my own original to source for addition to WP?

 

[Dresden]

 

[Dresden]

 

[DotChem]

Could I crop your name out of that overly and make it my own original to source for addition to WP?

Yeah @Nagelfar no problem go ahead edit and use it as you see fit. But keep in mind it is the mono-subsituted piperazine not 3CPEP per se. So make sure you let your readers on WP knows that..

...benzyl analogues of MPH i.e.

have >5,000 Ki inhibition @ DAT

do you have original source? SAR paper (not patents !) the original peer-review paper of MPH and analogs SAR at DAT??

 

[Nagelfar]

Thanks DC

do you have original source? SAR paper (not patents !) the original peer-review paper of MPH and analogs SAR at DAT??

Axten, J. M.; Krim. L.; Kung, H. F.; Winkler, J. D. J. Org. Chem. 1998, 63, 9628.

-is the source quoted, for 86th page here

 

[klfiend]

I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea. Cannot find the original image at this point I lack good tools to explore this further but I am very curious.

 

[pharmakos]

I wonder what just increasing the length of the alkyl chain on NMDA would do. Would be very interesting if that alone could turn it into an antagonist.

 

[Solipsis]

It would, but it doesn't seem likely: in ACA's the optimal length is ethyl, longer than that (besides constraining in heteroring) and they simply get less potent. NMDA is an excitotoxin, if any of the SAR makes any sense a lengthy alkyl chain won't cause the aspartic acid derivative to bind without activation (i.e. antagonistic), but just have less affinity so a little less toxicity.
I realize there may be a different ruleset for antagonists, but at least for ACA's the pharmacophore and similarity to NMDA should be a match?

I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea. Cannot find the original image at this point I lack good tools to explore this further but I am very curious.

Not a bad idea, I've fantasized about different ways to mimick NMDA than the typical groups in arylcyclohexylamines, but not what you posted.
However counting from one carboxylic acid to another, you seem to have one added spacer when comparing to NMDA, so that =O oxo group you have on 3 (a la MXE) would have to be on 2-position now. In MXE and other arylcyclohexylamines part of the phenyl ring (from the 2-position to the 3-position) plays a role similar to that of the oxo.
Now that you made the phenyl ring into a cyclohexyl ring, that is not true anymore, so the electron-rich moiety will now have to stick out, but closer by than the 3 position.

Am I explaining my idea well or should I draw it? (Not long ago in this thread molecules were posted that intentionally had different spacing - more specifically of the amine position compared to the carboxylic acid like functions, and who knows if some of these would work)

Another thing is that I would not be surprised if the arylcyclohexylamines work well in part because of an aromatic site in the channel that pi-stacks with the phenyl ring, good for sticky binding and coordination. Off the top of my head, MK-801 ketamine DXM diphenidine they are all aromatic.

 

[pharmakos]

It would, but it doesn't seem likely: in ACA's the optimal length is ethyl, longer than that (besides constraining in heteroring) and they simply get less potent. NMDA is an excitotoxin, if any of the SAR makes any sense a lengthy alkyl chain won't cause the aspartic acid derivative to bind without activation (i.e. antagonistic), but just have less affinity so a little less toxicity.
I realize there may be a different ruleset for antagonists, but at least for ACA's the pharmacophore and similarity to NMDA should be a match?

efficacy as an agonist/antagonist isn't equivalent to binding affinity, is it? afaik, there's a correlation but it isn't the whole story.

are ACAs fully antagonists at the NMDA receptor, or are some of them mixed agonists/antagonists? if some are mixed, then the potential for NMDA-analogues as dissociatives seems more likely to me. having a hard time googling the answer myself.

n-ethyl-d-aspartate exists, CAS 5555-23-7. seems to also be called n-ethylaspartic acid. can't find any literature on it, tho, just chem supply stuff. only one google hit on the propyl.

sounds like a decent research project for someone in the position to do such a thing.

 

[Solipsis]

Now that I think of it, NMDA binds at the glutamate binding site while ACAs bind at an allosteric site, the PCP site - so that probably means all bets are off.. Sorry about that man

I must say that it always confuses me that there are those different binding sites but ACA's still mimic NMDA at another site than were NMDA binds to. And sometimes dissociatives have features that make no sense from a purely NMDA-overlaying point of view, so once again SAR breaks down at some point.

Way to go making it complicated, NMDA receptor. Well played

 

[pharmakos]

i knew that too but forgot as well lol.

in googling on NMDA analogues, found a couple NMDA-antagonists that are really close to NMDA itself in structure:

here's NMDA:

here's AP5:

here's AP7:

edit --

wow there's actually a lot of these, here's CGP-37849:

 

[white55]

This was probably already posted here, but can we make any changes to the cyclohexane ring in arylcyclohexylamines without losing activity?

I know changing the ring size (cylcopentyl, cycloheptyl) makes it totally inactive, but what about substitutions?

A few examples:

Silly bonus molecule:

I believe someone on bluelight said that you can put the keto group or a methyl group on position 4 and retain activity.

And there is also https://en.wikipedia.org/wiki/Gacyclidine (although this is technically a thienylcyclohexylamine)

 

[aced126]

i knew that too but forgot as well lol.

in googling on NMDA analogues, found a couple NMDA-antagonists that are really close to NMDA itself in structure:

here's NMDA:

here's AP5:

here's AP7:

edit --

wow there's actually a lot of these, here's CGP-37849:

All these analogues are only really useful for studying NMDA receptors in vitro; they are way too polar to cross BBB in vivo.

Indeed, one has to consider which binding spot the ligand in question is binding to, as different ligands binding to different binding sites have different implications.

 

[crmt28]

I saw an image of a overlay of an NMDA molecule overlaid a methoxetamine molecule and had this idea. Cannot find the original image at this point I lack good tools to explore this further but I am very curious.

This one? https://psychonautwiki.org/wiki/File:Dissociatives_w_-_glutamate.png

These also fit:

 

[adder]

The binding site of methoxetamine is different from glutamate's, so it doesn't make sense to compare their structures.

I believe someone on bluelight said that you can put the keto group or a methyl group on position 4 and retain activity

4-keto group dramatically increases affinity to opioids receptors especially if there is a tertiary amine present in the molecule. However, one modification of the cyclohexane ring that boosts the activity at NMDA receptors is 2-methyl group, (-)-trans-2-Me-PCP (phenyl trans to Me) is 5x more potent than PCP in vitro and 2x more potent in vivo, so perhaps: