• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

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

Nagelfar

Nagelfar

Bluelight Crew
Joined
Nov 23, 2007
Messages
2,527
Location
Vancouver, Washington USA
Recently I was looking at the salicyl-methylecgonine page on wikipedia (cocaine is benzoyl-methylecgonine), and considering what other benzoyls (not to be confused with "Benzos") could be substituted on the ecgonine molecule to make an active DRI of the cocaine type; what the benefits are that there would be, and how those would be enhanced. Also which ones would retain internal obstruction of the sodium voltage gated action potentials. (another, possibly unrelated interest is whether a calcium or potassium action potential is interchangable on a cocaine local/topical anathestic)

A list of many can be found:
http://en.wikipedia.org/wiki/Category:Benzoic_acids (immediately discounting the obvious that are either bereft of active targeting of anything or wouldn't penetrate the BBB; as contrast mediums etc.)

Due to salicylate intolerance (which is a: "pharmacological reaction, not an allergy") salicyl-methylecgonine would therefore IMO not be an ideal 'substituted benzoic cocaine analogue'. (BTW: Salicyl-methylecgonine is a trace natural metabolite of cocaine which is 3-10 times the potency of cocaine (think oxymorphone out of oxycodone) )

Not a benzoic but barbituric acid (FYI not barbituric acid as a salt to the base, as if I am not mistaken was once used with opiates particularly morphine: what I am bringing up in this topic, if anyone is not clarified, is adding to part of the organic compound itself as an artificially substituted element replacing a branch, link etc, not the salt added to the base, which commonly are for example hydrochloride or sulfate, though I am interesting in optimizing those as well, that is not here my meaning for the uninitiated) ...*ahem* though not a benzoic, is an example of something besides salicylate that would have an overt effect with some contraindications, and possibly a speedballesque favorable effect in the form of anxiolysis. If there is an apparent potential effect to a benzoic class acid to replace the benzoic proper, that constitutes cocaine, that might be a good harm reduction alteration to the molecule (of course completely depending upon what that is) that would be the superior nature I am here visualizing.

The 'anasthetic taste' of the cocaine drug, and possibly additionally the methyl benzoate taste (as a byproduct of the natural decay of the cocaine molecule which is used as a perfume fixative), makes me consider the potential of Vanillic acid out of the benzoics too, just fittingly if nothing more.

Anyone with a good understanding of these classes and their viability care to elaborate or add your knowledge in this form of SAR alteration?
 
Last edited:
Go for para-halogenated benzoates. They work to increase potency on the phenyltropanes, and fluorobenzoate is already in 4-fluoro-tropacocaine, which probably would be more potent than cocaine if it didn't lack the other ester...

Furfurate would also be interesting.
 
Well, this is an exciting field of exploration, but what do you mean when you speak of replacing the benzoate portion with a salicylate? You mean simply an extra 2 aryl -OH there or what? I don't see the logic there, if so.

Some structures to illustrate your query could come in handy here.

One time, when quite high on cocaine, I drew out many different such possible structures on an old white wooden door that was off its hinges with a black Sharpie pen. One of which which stands out in my mind today is 3,4,5-trimethoxyphenyl-(C=O)-O-R. don't ask me why It's called outsider art.
 
dread said:
Go for para-halogenated benzoates. They work to increase potency on the phenyltropanes, and fluorobenzoate is already in 4-fluoro-tropacocaine, which probably would be more potent than cocaine if it didn't lack the other ester...
Click to expand...

Same trends don't apply with the benzoates it seems, from the little research that has been done. Only the 2'-hydroxy and 2'-acetoxy derivatives are significantly more potent than cocaine, 4'-hydroxy is only slightly stronger, 3'-hydroxy much weaker. 4'-iodo is much less potent (but can be partially "rescued" by adding a 2'-hydroxy group) and 4'-fluoro is less potent at inhibiting dopamine reuptake but is much more potent as a serotonin reuptake inhibitor. Both the 1-naphthoyl and 2-naphthoyl derivatives are weaker than cocaine. See Singh S, Chem Rev 2000;100:925.
 
Dresden said:
Well, this is an exciting field of exploration, but what do you mean when you speak of replacing the benzoate portion with a salicylate? You mean simply an extra 2 aryl -OH there or what? I don't see the logic there, if so.

Some structures to illustrate your query could come in handy here.

One time, when quite high on cocaine, I drew out many different such possible structures on an old white wooden door that was off its hinges with a black Sharpie pen. One of which which stands out in my mind today is 3,4,5-trimethoxyphenyl-(C=O)-O-R. don't ask me why It's called outsider art.
Click to expand...

http://en.wikipedia.org/wiki/Salicylmethylecgonine

It's a natural active metabolite.

mad_scientist said:
Same trends don't apply with the benzoates it seems, from the little research that has been done. Only the 2'-hydroxy and 2'-acetoxy derivatives are significantly more potent than cocaine, 4'-hydroxy is only slightly stronger, 3'-hydroxy much weaker. 4'-iodo is much less potent (but can be partially "rescued" by adding a 2'-hydroxy group) and 4'-fluoro is less potent at inhibiting dopamine reuptake but is much more potent as a serotonin reuptake inhibitor. Both the 1-naphthoyl and 2-naphthoyl derivatives are weaker than cocaine. See Singh S, Chem Rev 2000;100:925.
Click to expand...

This is the kind of sourcing and information that I am quite thankful for and love the community at bluelight.ru for being able to dish out. Thank you.
 
2'-MeO aryl homologue hmm? Wouldn't know, is there any research on this? It's hard to find info on cocaine analogues that aren't phenyltropanes or pure anaesthetics so anything in that category here would be welcome.
 
The 2 prime OH one is simply not getting through the blood brain barrier as well as this other one.
 
2'OH benzoic acid- salicylic is internally hydrogen bonded which masks the polarity of the OH group. salicylic acid is easily capable of crossing the blood brain barrier
 
Nagelfar said:
So can Salicyl-methylecgonine cross the BBB or not? If not is it metabolized to such in the brain from cocaine (Benzoyl-methylecgonine) anyway?
Click to expand...

most likely yes it would cross. however salicoyl esters are much more susceptible to hydrolysis than benzoyl esters.
it seems unlikely that any metabolic process would lead to salicoyl methyl ecgonine being made from cocaine
 
I guess the main 'splinter in in the butt' (homeland expression) about cocaine is it's short half life due to the rather unstable nature of the compound which gets metabolized into ecgonine and benzoic acid.
If we could switch that freaking ester oxygen with something more robust, we could possibly overcome this bugger (also this would make it orally active).

Any suggestions?
 
/navarone/ said:
I guess the main 'splinter in in the butt' (homeland expression) about cocaine is it's short half life due to the rather unstable nature of the compound which gets metabolized into ecgonine and benzoic acid.
If we could switch that freaking ester oxygen with something more robust, we could possibly overcome this bugger (also this would make it orally active).

Any suggestions?
Click to expand...

mostly it is not the benzoyl ester that is cleaved, rather the methyl ester to give benzoylecognine. Replacing the methyl with isopropyl or ethyl gives more potent drugs with a longer duration of action but higher toxicity.
 
Nagelfar said:
2'-MeO aryl homologue hmm? Wouldn't know, is there any research on this? It's hard to find info on cocaine analogues that aren't phenyltropanes or pure anaesthetics so anything in that category here would be welcome.
Click to expand...

The 2'-MeO-derivative of cocaine was made and tested in vitro. The IC50 was far too high to suggest activity (46654 +/- 840 nM, in contrary to cocaine itself with IC50 = 249 +/- 37; the 2'-OH-derivative had an IC50 of 25 +/- 4 nM).
Ref: Arch Pharm 2001, 334(8-9), p.275

Peace! - Murphy
 
Last edited:
Thank you Murphy.

vecktor said:
most likely yes it would cross. however salicoyl esters are much more susceptible to hydrolysis than benzoyl esters.
it seems unlikely that any metabolic process would lead to salicoyl methyl ecgonine being made from cocaine
Click to expand...

The references sourced and given of it being a metabolite are: 1. ^ Singh S, Basmadjian GP, Avor K, Pouw B, Seale TW. A convenient synthesis of 2'- or 4'-hydroxycocaine. Synthetic Communications. 1997;27(22):4003-4012.
2. ^ el-Moselhy TF, Avor KS, Basmadjian GP. 2'-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies. Archiv der Pharmazie (Weinheim). 2001 Sep;334(8-9):275-8. PMID 11688137
3. ^ Seale TW, Avor K, Singh S, Hall N, Chan HM, Basmadjian GP. 2'-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding. Neuroreport. 1997 Nov 10;8 (16):3571-5. PMID 9427328

---

PS; could anybody upload how one could draw, if it is tenable, a vanillic acid branch where the benzoyl branch on the cocaine molecule is in placement of it somewhat like the salicyl we've discussed? I just figured a thread became more interesting when we begin to go the direction of 2D novel molecule drawings from posters. ;j (when they're tenable and make sense and are made by the knowledgeable of course. : p Let's at least get some images of people's non-phenyltropane cocaine SAR substitutions, preferably benzoic family as per this thread but as long as it is not of the phenyltropane variety I am not too biased)
 
Last edited:
You asked for a picture of methylvanillylecgonine, right?




And it's only reference:

Smith, R. Martin; Poquette, Michael A.; Smith, Paula J.
"Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine."
Journal of Analytical Toxicology 1984, 8(1), pp.29-34


Peace! - Murphy
 
MurphyClox said:
You asked for a picture of methylvanillylecgonine, right?




And it's only reference:

Smith, R. Martin; Poquette, Michael A.; Smith, Paula J.
"Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine."
Journal of Analytical Toxicology 1984, 8(1), pp.29-34


Peace! - Murphy
Click to expand...

LOL it exists! Vanilla binds in vivo with cocaine. OK, makes sense but I wasn't expecting it.
 
You must log in or register to reply here.
Top