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I Like to Draw Pictures of Random Molecules

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5-methylthio-3-(dimethylaminoethyl)indole.png
 
aced126 said:
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.
Click to expand...

The entropy vs ring strain do clear things up regarding which reactions are more favorable in this case!

adder said:
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.
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That's a lot of variables to consider.. this ring opening and all the possible side-reactions really opened up a can of worms.

(Also somewhere Gollum creamed his pants reading that ^)



aced126 said:
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?
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Speaking of which: also dimerization to form other pyrazine derivatives? Polymerization crapping your product? I don't know if I see a way for that here, are the ingredients there?

IIRC with experimenting on bk-2C-B a little bit, if purple discoloration is any indicator (I guess what you expect with such conjugated systems?) that kind of alpha amino ketone dimerization is especially base-driven but I really fuzzy on that. Should also happen spontanously under influence of oxygen..

5-MeS-DMT should be in tihkal i believe?
 
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Looks stinky lol.
The cmpds themself seems odorless but those remaining synthetic reagents impurity is ouch...
Even ppm impurity seems so.. ugh :) (try sniffing aromatic thiols)
 
DRUG DESIGN:
Here is the crystal structure (the 3D) of cocaine bound to the drosophila dopamine transporter DAT"

4XP4_image%202_zpsvoksna13.png


Too much details but here is a close up view:

4XP4_image%201_zps7fqsx6tm.png


The 2 blue dots and 1 green dot are the 2 sodium Na+ and 1 Chloride Cl- co-transported along with the dopamine substrate. The extra sodium used to depolorize the neurons by increasing the charge inside. I mean it transports 2Na+ and 1 Cl-(net charge = +1). Dopamine, d-AMPH, methamphetamine, RTI-55, b-CFT ..etc all bind to the same site similarly with some minors difference but not as tight as cocaine (check out their structures with DAT on pubmed). I dont know about MPH and cathinones. No structures yet but I guess it should be same!
The dotted line shows the drug NHMe+ making contact with a COO- of the DAT transporter making a salt like interaction (like in ammonnium acetate).

Notice how the phenyl ring of cocaine is sandwiched between 3 phenyl rings of the aminoacids of the DAT protein. Since there is more rooms, that explain why a bigger group there like a nathpthyl of CFT tropanes is even better or dichlorophenyl. it fills the space and interact more tightly with the tranpsorter. Not much room to play around with the tropane side thouh as it sits on a narrow channel made up of the protein. the ester COOMe of cocaine points toward the solvent outside the drug binding site so one can put a bunch of shit there without affecting binding. The bridge CH2CH2 of the tropane seems useless maybe just orienting the rest of the molecule.
So if If you were to design analogs of cocaine (at least in so far as DAT inhibition is concerned) your best bet is the phenyl side of the drug. Disclaimer: all this is available public information of the pubmed NIH website here:

"4XP4: X-ray Structure of Drosophila Dopamine Transporter in Complex With Cocaine: https://www.ncbi.nlm.nih.gov/Structure/pdb/4XP4 "

They have nice 3D viewer software way much better than these static pictures here where you can view in movie-like turning zooming eliminating adding ..whatever.. pretty cool! check'em out:
 
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Both of the two previous submissions are loosely related to the seductive arecoline.

N-methyl-3-carbomethoxy-1,2,5,6-tetrahydropyridine.png
 
In fact, the first

N-methyl-3-carbomethoxy-4-(4-methylphenyl)piperidine.png


could be dubbed 3,4-dihydro-4-(4-methylphenyl)-arecoline!
 
DotChem said:
Not quite @aced126. This is a about twice as potent as cocaine (as DAT NET and SERT reuptake inhibitor)..!
imgsrv.fcgi


https://pubchem.ncbi.nlm.nih.gov/compounds/44337739#section=Top
or this even more active:

imgsrv.fcgi

https://pubchem.ncbi.nlm.nih.gov/compounds/44337825#section=Top

But I guess it is hard to compare since a Chlorophenyl replace the benzoate ester of cocaine and a secondary amine replacing the NMe in these cases.
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This is a big finding and I'm surprised I didn't know about this. This stems a new set of DRIs - why haven't more of these been made by RC suppliers?
 
^ Synthetically the difference between phenyltropanes and those 4-aryl-3-carboalkoxypiperidines is huge IMO. I don't know if there are any short-acting phenyltropanes, but if we limit ourselves to the simplest 2-carboalkoxy-3-aryltropanes, they are all long-acting stimulants which most possibly makes them poor recreational drugs which combined with not necessarily cheap common substrate makes them not attractive as "RC's".

The piperidines might as well be more like SSRI/SNRI antidepressant with little recreational value, they might have been tested in small groups of volunteers and turned out not interesting.
 
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