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Structurally simple cocaine analogs
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Beagle
Member posted 06-18-99 10:01 PM
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This is one of the most promising area of research on cocaine analogs that I’ve come across. In the following ref, the authors were attempting to come up with an equivalent of methadone for cocaine addicts. That is, a
substance that would have some of the effects of cocaine without all the euphoria (Coke-Lite®, I guess it will be called). The research was based on some work done in ’73
(by Clarke) in which a series of similar compounds was made and found not to cause stimulation in mice (i.e. no fun). However, in this study, the compounds were found to be up to 30 times the potency of cocaine in blocking dopamine transport or binding of cocaine to its receptor. So the results are rather confusing. Possibly the researchers have actually found a lead in their search for coke-adone, or maybe they have found a series of ridiculously easy to synthesize highly potent coke analogs. Either way,
interesting work. Currently they are shooting up monkeys to see if they like it or not, but it may be years before they publish their work. Maybe someone out there could help them
out. I always say, never send a monkey to do a man’s work.
J Med Chem 1998 May 21;41(11):1962-9
Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton.
In this paper, a series of structurally reduced cocaine analogs are synthesized in which 2 carbons and an ester group have been removed from the tropane skeleton, giving 4-
phenyl-piperidines with an ester group at the 3-position. The most active compound in their series is about 30 times the potency of cocaine (in blocking dopamine uptake). The
synthesis is much easier than any other active cocaine analog, and starts from non-exotic reagents.
The authors start with arecoline (the active compound in betel nut: N-methyl-piperidine-3-carboxylic acid methyl
ester with a double bond between the 3 and 4 positions). Reaction of this with 4-chlorophenyl magnesium bromide gives the final compound. This synthesis yields a mixture of isomers, which the authors resolve with dibenzoyl tartaric acids, but this is not strictly necessary since each of the isomers are active. Arecoline is a fairly cheap starting material, $80/50g from Aldrich. Also, I think that it is used in veterinary medicine.
So here is the outline of the synthesis:
To a solution of 166ml of 1M 4-
chlorophenylmagnesium bromine in 700ml ether was added 12.9g of arecoline freebase in 300ml ether at -10 C. The mix was stirred at -10 for 30 min, poured onto ice and
treated with 200ml of 10% HCl. The aqueous layer was separated, washed with 200ml ether, cooled in an ice bath, and 100ml of saturated sodium bicarb. solution added. The
solution was extracted with 2x 100ml of ether, washed with brine, dried, and concentrated in vacuo. The crude mixture
was crystallized from EtOAc/hexane to give racemic cis-
isomer as a white solid (5g, 22%). Additional product, as well as the trans isomer was obtained by flash chromatography of the mother liquor.
Alternatively, it looks like that 4-piperidone that you fentanyl-heads have been dreaming about could also be used
to synthesize these compounds. I picture reaction of 4-piperidone with e.g. methyl chloroformate to give piperidone 3-methylcarboxylate (hey drone: enolate
chemistry!). This could then be reduced to the alcohol, and dehydrated to give arecoline. Or the piperidone 3-
methylcarboxylate could be reacted with phenylmagnesium bromide, dehydrated, and reduced to give the final compound. Note the use of one precursor to make both highly
potent opiate and cocaine analogs. Talk about speedballs!
Or what about starting from nicotinic acid (pyridine-3-carboxylate; a B-vitamin)? That should be cheap as dirt. Seems to me that reaction with phenyllithium would give 4-
phenyl-3-carboxyl-tetrahydropyridine, which would only need esterification and reduction to give the final compound. Or maybe there would be a better way to start from nicotinic
acid?
In the last two proposed syntheses, care would need to be taken to avoid formation of a potentially nerotoxic MPTP analog!
Seedcrystal
Member posted 06-23-99 09:19 PM
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Wow I've often had such thoughts myself with the arecolne! I never took it seriously because for some reason I thought their might be problems with the phenyl group bonding to the 2 position.
Thanks you just made my day.
I'll look that ref up.
BTW don't believe all the no abuse potential crap. I know people who get off on methadone, the only reason it isn't very abusable is because of its long half-life.
Seedcrystal
Member posted 06-23-99 10:20 PM
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I guess a grignard would be specific to the 4 position, I was thinking of a benzoate. Do you have any info on the pharmacology of the bare phenyl anolog without the chlorine?
Beagle
Member posted 06-24-99 09:04 AM
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I believe that the non-chlorinated phenyl compound was in the original study (JMC '73, 16, 1260) and was found not to increase locomotor stimulation in mice. But the effect of the chlorine in these compounds parallels that seen in the WIN series cocaine analogs from which they are derived. That is, there is the same 20-30 fold increase in activity from adding the chlorine.
Siegfried
Member posted 07-22-99 12:33 PM
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And what about the 4-Fluorophenyl analog ... The 4-Fluorophenyl analog of cocaine ( 4-fluorophenyl group instead the benzoate group ) is very much potent than normal cocaine !
So the 4-Fluorophenyl-3-(methylcarboxylate)- N-methyl-piperidine , must be very very potent i guess !!
prickleberry
Member posted 07-22-99 01:46 PM
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Making a cocaine analogue is all fine and dandy, but I don't see how a psychologically addictive drug like cocaine can be substituted for another less powerful drug to help cure addiction. The only way to get off psychologically addictive drugs is gradual reduction and a want to to it. Substituting another drug won't fool anyone. Nothing can replace the high that is given by cocaine, if a less powerful drug is given to the addict in place of regular coke, naturally the addict will seek more of the substitute to get the same effect.
Prickleberry out..
Siegfried
Member posted 07-23-99 01:24 PM
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Another question :
Does they spoke about the benzoate analog , it would be very similar to coke .
And what about the ethyl ester , ethyl ester of coke ( cocaethylene ) is much potent than coke .
Excuse my rusty english
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