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Substituted Benzoic acids as cocaine analogues (not phenyls making phenyltropanes)

So would Salicylmethylecgonine be an in vivo metabolite of cocaine's use in conjunction with aspirin then, or is it just by natural process that it comes about or...(?)
 
*bump*

OK, I've started some threads on lipophilicity and hydrophilicity, but to put it into a drug context this old thread of mine seems a good starting point, which is one of the reasons I've brought up benzoyls in those other threads. Could cocaine be made even more hydrophilic with a substitution to the benzoyl group and even more lipophilic with a substitution/alteration of the tropane? I'd love to see more additions to ideas in the vein of this thread for cocaine particularly.
 
You seem kind of confused on the issue - I suggest you read up on some organic chemistry tetbooks. "Hydrophilic" and "lipophilic" are two opposite ends of the spectrum.

What exactly are you aiming for? A more selective DAT binder than cocaine? A perceptually "better", more abusable drug?
 
sekio said:
You seem kind of confused on the issue - I suggest you read up on some organic chemistry tetbooks. "Hydrophilic" and "lipophilic" are two opposite ends of the spectrum.

What exactly are you aiming for? A more selective DAT binder than cocaine? A perceptually "better", more abusable drug?
Click to expand...

Cocaine is apparently both "Hydrophilic and lipophilic" due to how it blocks sodium action potentials.

Any number of things, but here specifically: A faster onset, even if that precludes a shorter duration of action
 
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Cocaine's onset is already incredibly fast, esp. when IV'd or smoked. The only bit that's hydrophilic on cocaine are the ester linkages - they're needed for anesthetic action at the sodium channel - but overall the molecule is very lipophilic, especially in the free base form.

Exchanging the benzoyl ester for a dihalophenyl group is probably your best bet at increasing speed of onset, but I bet 2' acetoxy cocaine would be just as good.
 
sekio said:
The only bit that's hydrophilic on cocaine are the ester linkages - they're needed for anesthetic action at the sodium channel - but overall the molecule is very lipophilic, especially in the free base form.
Click to expand...

The protonated form must be fairly hydrophilic from those linkages alone though, correct? Just from how instantly it disappears in water. I hear that pure cocaine even slowly evaporates into the open air from indoor levels of moisture.

sekio said:
Exchanging the benzoyl ester for a dihalophenyl group is probably your best bet at increasing speed of onset, but I bet 2' acetoxy cocaine would be just as good.
Click to expand...

Interesting thank you. Anyone be willing to draw them?
 
NHIAS.png


The protonated form of cocaine is soluble because of the free quaternary ammonium proton (that is added in the process of protonation). The ClogP for the protonated form is actually higher.
 
sekio said:
NHIAS.png


The protonated form of cocaine is soluble because of the free quaternary ammonium proton (that is added in the process of protonation). The ClogP for the protonated form is actually higher.
Click to expand...

Thank you again sekio. So is that saying the protonated form is actually more hydrophobic? Would this mean hydrophilicity and water solubility are not necessarily related?

I think 2-position acetoxy cocaine is the basis I've been looking for. Though would such a conformation exclude or hamper the 3 & 4 positions from the halogens, if not reduced to a phenyl? What about adding the 2-acetoxy and the 34 dihalo on a benzoyl?

Edit: on second thought about 2'-acetoxy-, it appears that it would increase NE affinity too much in comparison to DAT affinity. Some other substitution to alter that in addition, may be interesting though.
 
^ Are you sure? I know that pseudoephedrine hydrochloride dissolves in chloroform, but other than that, the only examples of ionic compounds dissolving in nonpolar solvents I know are salts of complexated metal ions, where the ligand masks the positive charge. (see 'purple benzene').
 
When I was talking about the "solubility" of a protonated quat. ammon. I was referring to the water solubility.

Most quaternary ammonium compounds, save for the seriously sterically hindered ones, are very sol. in water and much less so in chloroform, etc. - their free bases are usually (but not always, in the case of very polar cmpds. - explaining cocaine freebase's small but nonzero solubility in water) not soluble. To use your example, pseudoephedrine.HCl is only "sparingly" soluble in CHCl3 whereas it is much more freely sol. in water and light alcohols. I think that there's enough proton exchange going on via chloroform to cause solvation, but not in e.g. benzene.

The rule I like to work with is, use protic solvents (water, alcohol) for dissolving salts and aprotic solvents (ether/dichloromethane/naptha/hexane) for free bases and organics. There are some exceptions but in general this holds true. Acid-base extractions rely on the differential polarity of salts versus freebases.
 
^ Ok there was some confusion here... Was that a typo when you wrote that the partition coefficient is higher for protonated cocaine than for the freebase? The partition coefficient is higher for more nonpolar substances, right?
 
No, that wasn't a typo - though ClogP is the Calculated logP and not an actual measurement. It's suprising for me too but it might just be a consequence of how Chemdraw calculates it.

If it makes you feel any better, Chemdraw has a "normal logP" as well, and that goes down once you protonate a quaternary ammonium.
 
sekio said:
Here's a paper you may be interested in.
http://www.scribd.com/doc/35574021/...ture-Activity-Relationship-of-Cocaine-Analogs
Click to expand...

Thank you.

Cloning mutated chimeric dopamine transporters just to see how cocaine binds is sure some extreme direction of study.

Does anyone hypothesize that the local anesthetic function on cocaine contributes to any form of active transport within the CNS at all whatsoever?

EDIT: and I suppose the million dollar question is: has any DRI ever been shown to be favored over cocaine (as a more discerning "positive reinforcer") ever in the history of animal testing?
 
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