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Structure-Activity Relationships (SAR) of NMDA open-channel blockers

Jamshyd said:
How anticlimactic :(. I was hoping you amongst a handful of others as crazy about these things as I am to comment on my questions =D.
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Although I'd like to say hugo was correct in needing time to think about it, I'm afraid any lack of answers from me is because, at heart, I'm a lazy bastard. I will say for question 1 - think cathinone wher you have a primary amine & a keto group on the same molecule... (condensation reactions etc)
 
Interesting stuff. I was initially going more along the lines of studying the PCP-like arylcyclohexylamines, but they are of course rather "dirty" in their pharmacological actions compared to the "cleaner" ketamine, tiletamine and such...

Jamshyd, I will do some dockings on those compounds you posted. Pharmacology is super-fascinating to me... thanks for your input =D

Now here's an intriguing possibility:

KA_005.png


This comes up as having an ALOGps value of -3.38 (that's somewhere near typical LOG s values I would get for MK-801 from AutoDock. Testing on protein residues from NMDA subunits 3A and 3B typically would average in Lipophilicity from -3.4 to -3.9 or so, indicating a very high specificity for the receptor).. This compound might be similar. Not as potent, surely, but still potentially a beast of a dissociative anesthetic.

Can't really say I have a clue about the dopaminergic or sigma-agonist activity, though. Those definitely play a part in the manifestation of "dissociative" effects from these compounds. Especially the anesthesia. Mostly mediated by blockage of pain signals via NMDA receptors, but there has to be another set of factors at work as well. MK-801 (dizocilpine) has negligible analgesic/anesthetic effects... and it really screws up rats' brains in large doses. No proof of whether or not that really happens in humans. Not nearly enough testing/research has been done to this point... but I digress. I'm rambling too much; bye for now.
 
Ok, get a load of this chemwank... I put ketamine, tiletamine and lefetamine in a sack, tied it up, and a moment later these bastard children popped out... can I name them kefetamine and tifetamine? :D

kefetamine.png
 
In reference to Jamshyd's earlier post:

I would venture to guess that that 2-phenyl-(2-piperidino)cyclohexan-1-one (compound D) would be the most potent of the bunch...

your 2-(2,3-chloromethoxyphenyl)-(2-ethylamino)cyclohexan-1-one is probably not going to be very active, with both substitutions on the phenyl ring; perhaps with one or the other.

3-methoxy PCP is much more potent than 4-methoxy PCP, so perhaps a 3-methoxy substituent isn't so bad...

Of course I'm not looking to actually make or taste any of this, and I most assuredly am not going to sell/deal any of it. That would just be outright completely idiotic; potency therefore matters less to me than whether or not a given hypothetical compound is active or not... it's just an exercise in interest and curiosity.
 
dread said:
Ok, get a load of this chemwank... I put ketamine, tiletamine and lefetamine in a sack, tied it up, and a moment later these bastard children popped out... can I name them kefetamine and tifetamine? :D

kefetamine.png
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Sure, why not... not really sure what the "chemwank" part means... I don't really randomly pull chemicals out of my ass when I do this. It's done with logic and reason behind it. Granted, the logic may perhaps be flawed in some cases, but at least I try.
 
Chemical masturbation, ie. posting structures that haven't been made and speculating on their activity. ;)

Sure there's logic behind it, but in the end it's all just speculation, and no one can actually know how the compounds would work until someone makes and tests them...
 
Thanks for your input, cosmo.

So I assume you would agree that one will have to chose one ring substitution, so compound "C" in my chart is not viable. In that case, I'd go for the 2-halo substitution, as it seems to be key to Ketamine's beauty.

That said, I am under the impression that the primary function of the 3-MeO substitution seems to be increasing opioid affinity? (I gather from FnB's suggestion). I personally felt 3-MeO-PCP did not have any opiate feeling to it.

And yes, the only use for increasing Ketamine's potency is for reducing toxicity.

Btw, it recently occurred to me that a ketamine analogue of PCPy might be interesting, as 3-MeO-PCPy is definitely a curiosity.

But for now, I am dying for the day n-Et-Norketamine is produced, and wouldn't be sad if a fluoro or bromo analogue of plain Ket is produced.
 
Btw, I am wondering why you seem to be attracted to things like Tiletamine and Dizocilipine. Everything I heard about both screams nightmares.
 
Tiletamine isn't a nightmare, just a rather rough & ready version of ketamine. Ket is smooth and inhabits a rather warm & friendly place whereas tiletamine can be bleak & scary, but even the non scary experiences seem to have no emotional resonance. The thienyl group makes it a more potent dopaminergic, but how this becomes bleak & industrial in feeling is beyond me.

After having tasted tiletamine I would have no desire to try TCP or TCE (or there cyclohexanone equivalents)
 
TCE (or there cyclohexanone equivalents)
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But but... isn't the cyclohexanone equivalent of TCE tiletamine?

So what you're saying is, after having tasted tiletamine you would have no desire to try tiletamine?
 
Jam, but you didn't try Tiletamin personally? Knowing that you respond quite differently than most people to those chemicals, I could imagine that you might like it (of course still behind K lol), it sure has a strong anestethic/analgetic effect (gathering from the few available human reports) which you're after.
 
indeed "Doctor T" is very very heavily dissociative, with not quite so much of the "psychedelic" type effect - at least from what I've heard - never tasted the stuff myself, although I really want to sometime soon. I'll probably just make 0.125-0.250 mols. for myself, seeing as how I'm not a veterinarian, or friends with any veterinarians for that matter.
 
say, what do you guys think about using an N-methylated piperazine ring instead of piperidine or pyrrolidine?

As in "PCPz", I guess you'd call it: 1-(1-(4-(phenylcyclohexyl) N-methyl piperazine..

always wondered about that.

The article from Clin. Toxicology in 1976 by Drs. Shulgin and Mac Lean suggests that an N-methyl piperazino moiety would maintain activity in a 6-6-6 or 6-5-6 cyclic system.

Another compound that intrigues me is that of

1-(vinyl)cyclohexylpiperidine, or "VCP".. Shulgin and Mac Lean refer in their article to compounds that were studied in the 50s and 60s that had the phenyl moiety replaced with "benzyl, vinyl, allyl, acetyl, enyl, and cyano groups" and that they "appear to be similar in potency"... intriguing stuff indeed. Literally hundreds to thousands of compounds could potentially be made in the arylcyclohexylamine department alone. It's exciting to "chemically masturbate" like this, but you have to "go all the way" and achieve a fully synthetic neural penetration (chemical brain sex) if you really want to know what it's all about... =D
 
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