I Like to Draw Pictures of Random Molecules

[Ire206]

^^ Definitely seems as though the structures of opioids and NMDA antagonists are closely linked, DXM to Morphine and Diphenidine to Lefetamine, MT-45 etc.

Anyway, drew up a few basic molecules I had thought up, tried to get the naming the least whack as I could.

After drawing this I found a molecule extremely similar, but with a 4-methyl substitution, basically a-PVP to Pyrovalerone, called O-2556. I went with O-2555 for this as there wasnt anything with this name in the paper.
Apparently it should have reasonable action at DAT and NET...

Naphyrone / N-EthylPentedrone crossover. Expected SNDRI due to the naphthalene, as Naphyrone was the only pyrrolidine stimulant with any activity on SERT, at least in 1 detailed study of Pyrovalerone SARs

5-Amino Phenmetrazine. 4-Methyl Aminorex but with an extra carbon on the oxazoline ring, changing it to an oxazine I think.

1-Formyl-AL-LSZ. Another basic meshing of a few lysergamides.

 

[Solipsis]

^^ Definitely seems as though the structures of opioids and NMDA antagonists are closely linked,

Opioid receptors and NMDA receptors are also closely linked.. they colocalize on neurons in a lot of brain regions..

 

[adder]

I suppose we need moar valerones. According to one study (J Med Chem. 2006 February 23; 49(4): 1420–1432) the racemic isohexyl analogue of pyrovalerone seems to be very close in affinity to DAT and NET to the more potent (S)-enantiomer of pyrovalerone itself, IC50 values are even more promising (for DA uptake 5.9 nM vs. 16.3 nM for (S)-pyrovalerone), we could be in for even more potent a-PiHP and MDPiHP (or a-PCP and MDPC - as they are analogues of alpha-pyrrolidinylcaprophenone, but the first one might be confusing). According to another study (ACS Chem. Neurosci. 2013, 4, 1524−1529) MDDMV (dimethylamino analogue of MDPV) has ~1/5x the affinity of MDPV to DAT, so MDDEV seems a reasonable option to consider.

 

[TrippyZebra]

was reading about astatine and wondered if it would produce similar effects to 2c-I if you made 2c-At. Would this be deadly or even possible to make considering how rare astatine is?

 

[Solipsis]

physically impossible is not economically impossible.. my guess is it should be possible but unrealistic to attempt to make a reasonable quantity, also it's not that reactive so I'm not sure if it will even bind to carbon in the 2C-I synthesis manner. I imagine you might have to use some tricks?
Was Alexander Litvenenko's drug of choice, i'm sure.

 

[TrippyZebra]

Cool thanks for the detailed answer. It sounds interesting if it could ever become a reality,*sigh* but a psychonaut can dream.:D

 

[adder]

I'm far from an expert in radiochemistry (I wonder why it has "chemistry" in its name even...), so I don't know how damaging consuming such a compound would be (or perhaps beneficial as supposedly small doses of radiation are), but why would you want to ingest a compound with an alpha-particle-emitting atom with a half-life of ~8 hours in it at all?

 

[Solipsis]

For the novelty of course.
Radiochemistry is about the chemistry of radioactive compounds or the influence the use of radiation has on chemistry... so it just doesn't really focus on the physics or the application is much about chemistry? I guess it's an overlap of the fields like physical chemistry, which isn't even nearly close enough about proper chemistry as I would like and I always hated the subject.. Radiochemistry is about a way to be able to calculate chemical reactions as is done in physical chemistry?

Say the dose is 40 mg in a 70 kg man, 0.10 mmol 2C-At with astatine-211 then you get 1.43 x 10e15 Bq radiation while in rats 8.4 x 10e8 Bq (also from At-211) at the same body mass (never seen a 70 kg rat though, apart from splinter from the Teenage Mutant Ninja Turtles - I guess that whole mutagen treated animal thing is writing on the wall...)
... that radiation caused changes and destruction to thyroid and lymphatic tissue..

So you would get 1.7 million times that toxic dose. It's ridiculously radioactive and toxic because of that short half life, like a juiced up plutonium during it's 15 minutes of fame.

(thanks wolfram alpha)

Other isotopes are considerably less radiotoxic though so it depends, but still it seems like quite enough to be a big problem - even 10 times less radiotoxicity is still way⁶ too much. I could be off here.

Where else can one go, from 2C-I? The iodine is the fourth, and the last of the so-called halogens, at the bottom of the classical periodic table. But, thanks to the miracles that have accompanied us into the nuclear age, there is a fifth halide now known, Astatine. All of its isotopes are radioactive, however, and it seems unlikely that there will ever be an entry (other than this one) for 2,5-dimethoxy-4-astatophenethylamine. What might be speculated as to its activity? Probably similar in potency to 2C-I, requiring maybe 10 or 20 milligrams. The duration would be dicey to measure, since the isotope with the longest known half-life is half decayed in about 8 hours, and the longest lived natural isotope (for those who insist on natural rather than man-made things) is half decayed in less than a minute. Two predictions would be pretty solid. You might have quite a job accumulating your 10 milligrams of Astatine, as the most that has so far been made at one time is only about 0.05 micrograms, approximately a millionth of the amount needed. And the second prediction? You would not survive the screaming radiation that would bombard you if you could get the needed 5 or 10 milligrams of radio-astatine onto that magic 4-position, and the resulting 2C-A into your tummy!

 

[TrippyZebra]

For the novelty of course.

Lol my thoughts exactly.

*Wow thanks for finding that didn't know Shulgin already covered it.

 

[sekio]

 

[aced126]

XR benzo - interesting

 

[Bagseed]

I like the intramolecular imine formation to create the ring. Pretty clever, will that happen in the stomach though?

 

[Solipsis]

Yes clever.. Will there be an equilibrium of the other (12-membered ring?) imine also being formed while/until lysine cleavage progresses? Or even various more possible imines? Would be an interesting dance.

I like the shape of that thiobarb orientation

Why not this by the way:

It's actually not trypsin / pepsin that would cleave something like this but aminopeptidases red blood cells, which begs to wonder if it is after the stomach you probably wouldn't get [quite as much] imine formation due to pH, isn't that azepine ring necessary for BZD binding?
Isn't your secondary amine metabolized by cytochrome P450's anyway?

 

[aced126]

I just realised the benzo has an amine rather than amide linker. If you were hoping for PLP-dependent aminotransferases to remove the lysine, I don't think that will work because those enzymes are substate specific and used in amino acid synthesis. I'm pretty sure it'll definitely only accept primary amines if anything. Of course CYP metabolism will dealkylate the amine but at a much slower rate I reckon. Also as Solipsis mentioned, imine formation might take a while in a neutral environment, so the compound might be mostly excreted before it actually gets a chance to cyclise.

 

[aced126]

Yes clever.. Will there be an equilibrium of the other (12-membered ring?) imine also being formed while/until lysine cleavage progresses? Or even various more possible imines? Would be an interesting dance.

I like the shape of that thiobarb orientation

Why not this by the way:

It's actually not trypsin / pepsin that would cleave something like this but aminopeptidases red blood cells, which begs to wonder if it is after the stomach you probably wouldn't get [quite as much] imine formation due to pH, isn't that azepine ring necessary for BZD binding?
Isn't your secondary amine metabolized by cytochrome P450's anyway?

Actually trypsin preferentially cleaves amide bonds where the carboxyl side of the bond is a positive Lys or Arg residue, so your compound fits. As I mentioned earlier, it would really be preferable if it gets hydrolysed in the stomach so the imine can form quickly under acid catalysis. But then that kind of defeats the whole purpose of the XR mechanism anyway.

Pretty sure the ring is necessary for binding activity.

Rings above size 7 are quite hard to make because of the entropic cost associated with their formations. There are several possible conformations that the free chain can adopt, making it less likely that the ring-forming conformation is adopted. They have no problem with enthalpy/stability though, as they have essentially no ring strain. On the contrary, for small rings it is the exact opposite - few possible conformations means ring formation is more likely, but the ring itself is highly strained making it unstable.

The ideal ring size is 5 or 6.

 

[adder]

The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.

Anyway, that's a bit carried away.

Radiochemistry is about the chemistry of radioactive compounds or the influence the use of radiation has on chemistry... so it just doesn't really focus on the physics or the application is much about chemistry? I guess it's an overlap of the fields like physical chemistry, which isn't even nearly close enough about proper chemistry as I would like and I always hated the subject.. Radiochemistry is about a way to be able to calculate chemical reactions as is done in physical chemistry?

I'm not sure if radiochemistry as a subject is that common outside of physical chemistry, but I had the pleasure of having it and it was mostly about memorizing how various counters are built and how they work with one of the most boring lab classes ever each one coming down to sitting and taking hundreds of measurements. I don't know why you would need a lab coat for that but it was mandatory. I still have an exam to take which is going to be fun for sure.

 

[aced126]

The strain energy actually does increase upwards from cyclohexane with cycloheptane having a similar ring strain energy to cyclopentane and the maximum being around cyclodecane or so, this is due to unfavourable eclipsed and flagpole interactions between C7 and C12-4 rings, and diminishing when the increasing ring size makes such interactions matter less and less. I'm sure the ring strain does matter as well beside long distance between two ends when they do meet and the whole to-be-the-ring structure takes a conformation close to that of the ring itself, it's probably hard to see for bigger rings as they would all typically need longer reaction times for the reaction to complete, but the strain must be the factor too, otherwise you would only need to increase reaction time to make it statistically possible for all the molecules to happen to be in the right conformation to close into a ring, right? In more complex organic compounds (I mean more complex than simple alpha-halo-omega-lithioalkane to be closed into a ring) the relationship between the ring size and the yield of a cyclization reaction is not going to be a simple one due to other steric and electronic factors, and often reaction medium as well, with reaching the energy level enough to warrant ring-formation impossible without degrading other moieties. Still, there are reactions in which bigger rings are formed in good yields under fairly mild conditions, e.g. Heck reaction and many other TM-catalyzed ones.

Anyway, that's a bit carried away.



I'm not sure if radiochemistry as a subject is that common outside of physical chemistry, but I had the pleasure of having it and it was mostly about memorizing how various counters are built and how they work with one of the most boring lab classes ever each one coming down to sitting and taking hundreds of measurements. I don't know why you would need a lab coat for that but it was mandatory. I still have an exam to take which is going to be fun for sure.

Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?

 

[sekio]

WHoops, I may have got the lysine backwards, Soli drew the 'correct' isomer that I really meant

 

[adder]

Surely if you increase reaction time in order to try and make a large ring forming reaction to go, the reactant will just react with other molecules instead of attacking itself?

Chances increase it will, yes, that's why in order to diminish such side reactions intramolecular cyclizations are often carried out in fairly dilute solutions.

 

[DotChem]

WHoops, I may have got the lysine backwards, Soli drew the 'correct' isomer that I really meant

would that be stable in solution? The amine at alfa position of the lysine will most likely attack the CO of the N(Me)CO amide to give a six membered pyrazinedione + N-Methyl-4-nitro-2-(2-fluoro)benzoyl-Aniline. The driving force beeing the 4-nitro-2-(2-fluoro)benzoyl strongly activates the amide toward nucleophilic attack and is an excellent leaving group + relative ease of intramolecular Rx to form stable 6-membered ring... but who knows?