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4-(ethylamino)-4-(3-methoxyphenyl)thian-2-one

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A direct replacement for MXE - LogP of MXE 2.09, LogP of thianone analogue 2.29. An oxygen is also possible but the Log P is under 2... then again, it cannot get oxidized. Adders study of the QSAR of PCP analogues suggests that a S=O might increase opioid activity so starts as MXE, ends as morphine? I don't know.

Eur. J. Med. Chem. 34 (1999) 125−135 'The search for TCP analogues binding to the low affinity PCP receptor sites in the rat cerebellum'

17 compounds are tested on forebrain single-site model & cerebellum single-site models.

They assign the IC50 of TCP to be 71.6 while the most active analogues most active isomer a value of 5.2, of the racemate, 5.5.

I think the ketone analogues are safer - part of a design is 'what would a stupid person do? So things you cannot eyeball are out. High potency of ANYTHING is out IMO. U47700 has already killed, I'm sure the fentanyl analogues have killed many. Always go for the option with the biggest TI. Amazingly, with the fentanyl class, sufentanil has a TI of over 12000 - it's SO mu1 selective that it doesn't interfere with respiration (mu2) but, that being the case, it would also lack any euphoria. Frankly, ALL opioids should come as 'jacks' so even an idiot can't screw up the dose on the most dangerous class of RC.
 
Do you mean thian-3-one?

I think the ketone analogues are safer - part of a design is 'what would a stupid person do?
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Mmm, but still, people in the UK have died under the influence of MXE as well. None of these drugs are going to be totally safe if they introduce major behavioural alterations, arguably even LSD is not 100% safe in that aspect.
 
So 4-thia-MXE? Your problem is that the standard alpha-ketol rearrangement synthesis of 2,2-disubstituted cyclohexanones will produce a mixture of 4-thia and 5-thia regioisomers. The other problem is that the synthesis could just fail.

I have a hard time believing this would be safer than MXE. In this case, we have to cross our fingers and hope that our metabolism ignores the thioether.
 
It may actually be a useful metabolic handle; thioethers are easily oxidised to quite polar sulfoxides and sulfones.
 
I've put a reference to the synthesis - I wasn't clear on what I meant by 'safer' - there is an example with an LD50 of 5.4 (compared to 72 for TCP) - Nothing that needs a scale is safe because too many idiots just eyeball the dose. That is my basic gospel, keep potency DOWN. There are already rodent LD50s on these (as mentioned in reference) and I don't really advocate anything with a TI below 80 or so. This may sound very old fashioned, but I guess my education was before any of the software was about. Crossfire DID appear in my last year but that was it.

NO drug is 100% safe but the simple replacement of a methylene with a thioether appears to offer another point for the body to remove the offending material. Believe me, the GC-MS of LOADS of the synthetic cannabinoid replacements have LOTS of dimers, trimers and polymers and I guess everyone saw the class WITH a known mutagen with an ester bridge. THAT is the class thats going to claim thousands of victims IMO.

S - yes, my bad.

I'm just concerned that the 1,2-diphenylethanamine class of NMDA antagonists has been messed with giving them AMPA affinity - seizures that way lie. That's why replacing the piperidine with an N-isopropyl is a positive move towards safety. I will dig up the paper on AMPA affinity for you. I guess 'lesser of 2 evils' was my thinking.
 
I guess everyone saw the class WITH a known mutagen with an ester bridge. THAT is the class thats going to claim thousands of victims IMO.
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I mean, to be fair, most of these synehteic cannabinoids I would not ingest orally, let alone pyrolize on plant matter... nothing about them seems attractive when cheap, high potency cannabis is ubiquitous in your area. The whole higher-efficacy-ligands-than-THC thing has been firmly demonstrated to make cannabinoids into thoroughly unsafe drugs in terms of not only overdose toxicity, but also the amazing, frankly crippling and even lethal, levels of withdrawla severity that they can precipitate. I guess it's an issue focused on heavy use, but even so, Snoop Dogg ain't exactly gonna seize out if he doesn't smoke his morning blunt, you know?

The well defined mutagenicity/toxicity of some of the pyrolysis/degradation products seems like just icing on the cake to drive the point home that these are fucking ligand probes and not pharmacy drugs!

I'm just concerned that the 1,2-diphenylethanamine class of NMDA antagonists has been messed with giving them AMPA affinity - seizures that way lie.
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I'd suspect the N-ethyl analog to be the worst, from anecdotal evidence. I've only tried MXP but it didn't seem unusually stimulating nor toxic (just a solid head fuck) even at... well, frankly silly 200-400mg in a session doses.
 
I think there's a *accidental* 2g ephenidine trip report on Erowid with no reported seizures. Sample size = 1, but I doubt it's harmful in sane doses (which are usually way below even 500mg).
 
No, plain ephenidine is not an issue... the issue with that is that the sulfate salt is snortable producing a much better experience but once again, lazy chemistry.

S - the 2-methoxy (MXP) was researched as an AMPA ligand. I don't think it gives a stimulating effect to cause seizures. Look at methaqualone (I put up a big list of patents). Anyone looking to design a new, high potency one ALSO has to read all the papers & patents on the AMPA ligands based on the quinazolinone scaffold so they aren't poisoning people. Optimally the toluene-ring has an EWG at the o or p position and a group at the o position to prevent free-rotation of the ring. Nitromethaqualone isn't the most potent by far, but it scared the bean-counters enough so little further research was carried out. The N-ethyl feels more stimulating because it has DRI properties.
 
These compounds smell horrible man, likewise they make undergo ring opening and alkylate DNA...
With that said the AMPA receptor and compounds for it that are said to be specific, appear to have high off label binding with many ACh/histamine receptors. Or this may be the receptor itself as well, it does so much. Some anecdotal reports of AMPA modulators claim psychadelic/deliriant activity, in a dysphoric manner.
In addition AMPA is a scary target man, it binds multiple cations and ligands and is extremely important for maintaining cell conductance alongside phosphorylation events... Look up AMPA trafficking.
 
Zeds(NCO2CH2CH3)2 said:
These compounds smell horrible man, likewise they make undergo ring opening and alkylate DNA...
With that said the AMPA receptor and compounds for it that are said to be specific, appear to have high off label binding with many ACh/histamine receptors. Or this may be the receptor itself as well, it does so much. Some anecdotal reports of AMPA modulators claim psychadelic/deliriant activity, in a dysphoric manner.
In addition AMPA is a scary target man, it binds multiple cations and ligands and is extremely important for maintaining cell conductance alongside phosphorylation events... Look up AMPA trafficking.
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It DOESN'T undergo ring-opening - the metabolites were accounted for. Oxidation is the fate of the S. the vapour-pressure of the S-containing precursor IS high, so it's not like thioacetone and I've smelt much worse. Considering that MXE was made in China, I doubt you would smell it from your locale ;-) Frankly, once again, it's an example of something the lazy RC chemists wouldn't take the trouble to make. I don't intend to post the simple stuff as I presume that isn't allowed. I DO recommend reading the paper as it gives the optimal ACE-class NMDA antagonist which is worth it to overlay with MK-801 in a very interesting manner.

I am fairly well versed on AMPA BUT my education IS from decades ago so I should read up on the new finds. As I said, after the Kreb cycle, it's the area I would be least likely to step.

May I recommend 'In The Pipeline' by Derek Lowe - keep up to date with what Big Pharma is upto. His 'things I will never work with' should raise some laughs.
 
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