• 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 | someguyontheinternet

Cocaine derivative lasting 3 days

C6H6

C6H6

Bluelighter
Joined
Jan 29, 2005
Messages
607
I've been reading up on cocaine analogs a bit lately and came across one intriguing compound which is briefly mentioned in one paper as not only being very potent, but also that it lasts up to 3 days in rodents because all ester functions are eliminated thus esterases can't break it down.

Maybe someone could retrieve the full paper and make it avaliable to us?
Bioorganic & Medicinal Chemistry Letters
Volume 3, Issue 6 , June 1993, Pages 1327-1332
http://tinyurl.com/dnhb6
 
Here's the structure which I forgot to insert in the above post:
attachment.php
 

Attachments

  • supercoke.gif
    supercoke.gif
    1.6 KB · Views: 1,056
Here is that article...

SAR of cocaine: further exploration of structural variations at the C-2 center provides compounds of subnanomolar binding potency.
Alan P. Kozikowski, Marinella Roberti, Kenneth M. Johnson, John S. Bergmann and Richard G. Ball
Bioorganic & Medicinal Chemistry Letters. 3(6), 1327-1332 (1993)
http://tinyurl.com/a42uo

...It seems as though replacing the 2beta-carbomethoxy with alkane or alkene gives very potent phenyltropanes with very long half lives.

For example, RTI-139 (3beta-(4-Chlorophenyl)-2beta-methyltropane) is about as potent as RTI-55 (beta-CIT, 3beta-(4-Iodophenyl)tropane-2beta-carboxylic acid methyl ester), but exceedingly long lasting... "Even at the conclusion of 20 h of behavioral observation, RTI-139 continued to increase locomotor activity..."

Sounded pretty rough on the rats though: "The highest dose of RTI-139 (8.6 mg/kg) was not tested, as this dose was lethal in two out of the first three animals tested."
 
Hmm... maybe I'm being too fancy here. But there was mention of Indatraline on this forum, but I can't seem to find it now. Anyways - Indatraline has two Cl atoms, and it is a potent and has action similiar to cocaine.

Do you think that chlorine as a ligand has anything to do with it? Or perhaps it alters its metabolism?

And btw, Is there a para-chloro (if I'm correct) version of Cocaine? (I mean cocaine with Cl attached to the same position on the phenyl ring as the molecule in your picture, but without any other modification)

Again, I'm pretty much making this out of the blue - I have nothing to base it on other than pattern.

EDIT: Btw.. since you mention this compound lasts 3 days... I'd imagine it may be toxic? Or at the very least, produces a horrific crash?
 
Last edited:
I have known about this for sometime. On the basis that p-chlorophenyl arecoline works well with a n-propyl group, I simply extrapolated this information over to phenyltropane on Bielstein and was able to retrieve the required information.

My only question with the vinylchloride is if it is intended for use in humans, are you sure that something like that will not be mutagenic? I mean just the word vinyl chloride sounds like something a bit reactive. Used by the industry for making PVC right?

If you dont feel like doing a Wittig reaction, just condense the aldehyde with methoxyamine to give methoxyimine.

If you dont feel like oxidizing the alcohol to an aldehyde, just make a lower alkyl ether such as ethyl ether.

If you dont feel like reducing the ester then just pick a 4-fluorophenyl ring to form WIN 35 428.
 
Last edited:
scarmani said:
...It seems as though replacing the 2beta-carbomethoxy with alkane or alkene gives very potent phenyltropanes with very long half lives.

For example, RTI-139 (3beta-(4-Chlorophenyl)-2beta-methyltropane) is about as potent as RTI-55 (beta-CIT, 3beta-(4-Iodophenyl)tropane-2beta-carboxylic acid methyl ester), but exceedingly long lasting... "Even at the conclusion of 20 h of behavioral observation, RTI-139 continued to increase locomotor activity..."

Sounded pretty rough on the rats though: "The highest dose of RTI-139 (8.6 mg/kg) was not tested, as this dose was lethal in two out of the first three animals tested."
Click to expand...
Thanks, Scarmani. Do you have the publication from which you took the above quotes at hand, too? I'd like to read the full paper.
 
Try reading this (if you havent already):

J. Med. Chem. 1995, 38, 3086-3093

http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/1995/38/i16/f_jm00016a012.pdf

Although the vinylchloride is clearly extremely potent, this paper shows that the vinylbenzene is actually slightly more potent, the Z configuration having the highest binding affinity. Hydrogenation of the alkene lead to a dramatic drop in potency, albeit still twice as potent as the unadulterated methylester.
 
Last edited:
With cocaine analogues, the upper of the two molecules below is reckoned at 60x potency of cocaine.

59655cocaine_analogues.JPG


Apparently the unesterified compound is also active (don't have actual figures to hand), bot only the one with the hydroxy group in the axial (as opposed to equatorial) position. Considering how easy it would be to get to that compound from tropanone via a grignard and anti-markovnikov addition to the double bond formed by dehydration, I'm surprised that it hasn't appeared on the illicit market (or maybe the market is just saturated by South American coke anyway).

As an interesting aside, the product of grignard addition to tropinone only needs esterification with propionic acid to produce a fairly potent opioid similar to MPPP. I'm not sure about this, but I think the 2 carbon bridge would prevent any of the dehydration compound from being metabolized to the MPPP+ analogue by MAO-B that caused all the problems for the people in N. California developing severe Parkinsons disease (although I'm fairly certain, I still wouldn't be the person to test the idea out!)
 
Mice, Rats, and Monkeys

This is the article that the quotes were from, it tests a number of phenytropanes (in mice actually) for locomotor stimulation / in-vivo potencies / time course of effects

Locomotor stimulant effects of novel phenyltropanes in the mouse.
Heather L. Kimmel, F. Ivy Carroll, Michael J. Kuhar
Drug and Alcohol Dependence 65, 25-36 (2001)
http://tinyurl.com/djgly


Another article with several additional compounds, this time in rats...

Cocaine-like discriminative stimulus effects of novel cocaine and 3-phenyltropane analogs in the rat.
Charles D. Cook, F. Ivy Carroll, Patrick M. Beardsley
Psychopharmacology 159, 58–63 (2001)
http://tinyurl.com/d6ew5


Indatraline is quite potent, cocaine-like and long-lasting but seems to produce nasty effects in the monkeys

Effects of the Long-Acting Monoamine Reuptake Inhibitor Indatraline on Cocaine Self-Administration in Rhesus Monkeys.
Charles D. Cook, F. Ivy Carroll, Patrick M. Beardsley
The Journal of Pharmacological and Experimental Therapeutics 291, 60–69 (1999)
http://tinyurl.com/dwm2y

"One monkey exhausted all its catheter sites before the effects of the highest dose of indatraline (0.56 mg/kg/day) were examined... grooming stereotypies (repetitive and unusually frequent grooming of or picking at skin or hair), buccal stereotypies (repetitive and unusually frequent movements of the tongue or mouth), visual checking (rapid, continuous shifts of visual field resulting from repetitive eye and/or head movements), and splayed legs (an unusual posture in which the monkey sits on the perch or floor of the cage with legs spread apart and turned outward)... stereotypies were observed in two of the three monkeys during indatraline availability, and substitution of the highest dose of 0.032 mg/kg/injection indatraline had to be terminated after 3 days in one monkey because of severe oral stereotypies."

The monkeys know best. I see them everywhere I look. They have all the right answers; they have taken control of the televisions.
 
@ F&b - are you sure about the structure of your first compound? The reverse ester seems quite unusual. A ref would be appreciated. Your second compound of course is quite well known as tropacocaine.

@ Scarmani - the problem with indatralin is that it's not only lasting too long, but also takes very long to kick in. It would be very easy to make if it was wothwhile.

The monkeys know best. I see them everywhere I look. They have all the right answers; they have taken control of the televisions.
Click to expand...
What else can you expect in a country where even the president is a monkey?
 
It's from the series 'The Alkaloids' - I'm working from an old tatty photocopy from many years ago. The thing that I found strange was that the unesterified compound (with the hydroxy group at the 2 position being the axial form) wasn't that much less potent than the esterified version
 
A bit off topic (again!) but tropanes can be the basis for a shitload of opioids as well (basically analogues of 4-substituted piperidines). The main examples are shown below

tropane_analogues_of_opiates.JPG


I do know that the pethedine and prodine (pethidine reverse esters like MPPP) analogues have been synthesised; I believe that they're about the same potency as their 4-phenylpiperidine parent derivs. and also share the same duration of action.

This means that starting from tropinone and phenylmagnesium bromide you can synthesis both cocaine-like drugs and opioids. Not bad if you consider that unlike N-methyl-4-piperidone, tropinone isn't a monitored chemical (or at least wasn't the last time I checked)

PS - I know fentanyl has a N-(2-phenethyl) group as opposed to a methyl group; it was just for illustrating a point
 
Tropinone is quite expensive though. I have seen the evidence that fenta-tropane is indeed highly potent but has the MPPP analog of tropane been published and was it a good agonist? I aim tempted to post my ideas on what one can do with tropinone but I woud like to know upon hydrogenation of an alkene bridge across the 2,3 position, how one can get the majority of the hydrogen being added from the endo point of attack.
 
Tropine is also associated with the benztropine branch of dopamine inhibitors. These stimulants have potent anticholinergic action and can be used treat Parkinsonism. However it has been reported that they are not thought to be reinforcing. "While these ligands did not bind potently at the NET and SERT, they bound to the muscarinic receptors with high affinity".
 
Last edited:
You can even make your own by extracting atropine, hydrolysing and oxidizing.

That's why I brought it up - fuck me, atropine is useful for something outside it's recognized medicinal uses (IMO it's def not anywhere near being a recreational/entheogenic drug!)

Bah! Beaten to the punchline!

Actually, oxidize then reduce the tropine and you get pseudotropine (it's the most stable/lowest free energy form) - that's just an esterification away from the 4-fluorobenzoyl analogue of tropacocaine - see one of my prev posts in this thread. It may only be 40% of the potency of cocaine, but after reading Le Junk's posts in OD, it'll still be on a par with the coke bought on the streets (and you know for def that it has no (meth)amphetamine or ephedrine mixed in with it)
 
Last edited:
Tropinone or N-nor-N-phenethyltropinone can be easily made in one step by the Robinson-Schöpf synthesis.

The tropine fentanyl analog is about 1/2 as potent as fentanyl if the two nitrogens are on the same side, and about the potency of morphine if the stereochemistry is reversed.
 
A simple esterification with 4-flurobenzoic acid on the tropinone would yield the corresponding tropacocaine would it not?

Just curious, but do the tropacocaines have an anaesthetic action like cocaine itself does? either way on that, I will find out in a week or two=D
 
3'-4'-dichloro-meperidine (pethidine / demorol)

Not sure if this is too far a-field... but might be interesting in light of F&B's comment about how you can synthesis both cocaine-like drugs and opioids from the same structural motif.

Structure–activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters.
Jill B. Rhoden, Maud Bouvet, Sari Izenwasser, Dean Wade, Stacey A. Lomenzoa and Mark L. Trudell
Bioorganic & Medicinal Chemistry 13, 5623–5634 (2005)
http://tinyurl.com/ccbq9
 
You must log in or register to reply here.
Top