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Immodium chemistry...

B

blase deviant

Bluelighter
Joined
May 9, 2004
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2,897
...is it possibly that this will become the next pseudoephedrine/meth situation? Is there anyway to turn this into something viable or is anyone working on it?

Not asking how, just asking if it's being done. Sorry if this is borderline.
 
i'm sure more than a couple have tried it, with less than startling results.

I don't think anyone'll find a route so simple bathtub chemists are going to be able to replicate
 
If anyone does, I sincerely hope it doesn't go mainstream like pseudo/meth. That would be fucking disaster.
 
tread very carefully as there is evidence that loperamide can form the kind of not fun substances related to MPTP and MPP+ and the reason it doesn't cause problems is it is poor at crossing the BBB. if say the hydroxy was acetylated then that would be good leaving group and you would have a substance that contains the N substituted phenyl tetrahydropyridine structure. bad news.
 
Have there been any studies on loperamide -> MPTP moiety that weren't underwritten by Pfizer? I've wanted as less biased source.
 
Loperamide.png


Lose the chlorine (NaBH4), with it being a reversed ester, acetyl? I think 1 longer.
Done that? Now it's 1/4 the potency of codeine. That bulky group on the piperidine ring means it binds to peripheral receptors much better than central ones. It replaced diphenoxylate, so see the similarities.
 
vecktor said:
tread very carefully as there is evidence that loperamide can form the kind of not fun substances related to MPTP and MPP+ and the reason it doesn't cause problems is it is poor at crossing the BBB. if say the hydroxy was acetylated then that would be good leaving group and you would have a substance that contains the N substituted phenyl tetrahydropyridine structure. bad news.
Click to expand...

I read a paper on analogues of MPP+, and the version with N-ethyl was much less neurotoxic, and the one with N-propyl was without any neurotoxic effect. So I think with such a bulky group as loperamide has it should be fairly safe?
 
ralf2 said:
I read a paper on analogues of MPP+, and the version with N-ethyl was much less neurotoxic, and the one with N-propyl was without any neurotoxic effect. So I think with such a bulky group as loperamide has it should be fairly safe?
Click to expand...



look at the wikipedia loperamide structure in Haribos post, now look at the structure of haloperidol (the notorious chemical cosh/straight jacket):
http://en.wikipedia.org/wiki/Haloperidol

haloperidol and loperamide both have bulky substituents on the piperidine nitrogen. haloperidol is known to produce an effective neurotoxin.

the abstracts on haloperidol neurotoxicity, and the formation of a MPP+ like neurotoxicity in this case the agent has been referred to as HPP+


http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=8071874&dopt=Citation

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8301579&dopt=Citation


Remember also that MPTP and MPP+ are without effect in rats.

and here is the reason why I suggest very careful exploration, a paper that documents the formation of a potentially neurotoxic metabolite form loperamide. If you modify loperamide so it can cross the BBB you are playing with fire. it could quite easily be neurotoxic:

IDENTIFICATION OF AN N-METHYL-4-PHENYLPYRIDINIUM-LIKE METABOLITE OF THE ANTIDIARRHEAL AGENT LOPERAMIDE IN HUMAN LIVER MICROSOMES: UNDERLYING REASON(S) FOR THE LACK OF NEUROTOXICITY DESPITE THE BIOACTIVATION EVENT
Click to expand...

http://dmd.aspetjournals.org/cgi/content/full/32/9/943

from what I can see, Haribo 1, is suggesting acetylating the hydroxyl group, brilliant. which is the better leaving group? OH or OAc?
As for loperamide neurotoxicty, I am not convinced either way but there are enough warning signs on this road to suggest travelling along it very slowly, perhaps even throwing a U turn.
 
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hussness said:
Have there been any studies on loperamide -> MPTP moiety that weren't underwritten by Pfizer? I've wanted as less biased source.
Click to expand...

In my opinion it is never wise to discount research due to its source, research coming from say pfizer which attacks Janssens product and a huge generic industry is likely to be much more solid than research produced by the University of nowheresville Alabama. simply because of what is at stake.

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=PubMed&list_uids=10717505&dopt=Citation
some french study.
if you read the whole paper it describes loperamide induced neurotoxicity and then death in piglets (they have incomplete BBB's).

there are also several papers which I don't have access to, though I'm sure I can find the citations. throw this in with the haloperidol evidence and perhaps it is better to be very cautious than blase and shaking :)
 
I was never suggesting that the results should be thrown out, I just wasn't aware of third-party replication.
 
hussness said:
I was never suggesting that the results should be thrown out, I just wasn't aware of third-party replication.
Click to expand...

apologies, I mis-interpreted what you said
 
this is the reason I've never liked the idea of piperidine-based opioids. There are better 'backbones' that don't have as much risk of neurotoxicity.

A brief search didn't find it, but I know I've seen either phenethylamine- or tryptamine- derived opioids. Got a feeling they'd be difficult to synth, though.
 
piperidine can be a backbone for just about anything, there are many good safe piperidines out there, i don't think you can say something would be bad cuz it's piperidine based. There are pcp analogs that are extremely potent opiates, of coarse there are many piperidine dissocaitives and stimulants aswell which are relatively safe
 
A bit like turning lead into GOLD. Its possible - just turns out its simpler to mine gold.

Seeing as there is no obvious & simple loperamide -> potent opioid reaction as soon as the chemistry starts getting complicated its probably easier to start modifying codeine or even starting from scratch.

Also I did read a study which concluded loperamide does have very mild analgesic properties IV but only at doses very close to toxic levels. Considering by taking megadoses your probably forcing the odd one or two molecules through the BBB the ratio of molecules causing unwanted effects becomes dangerous and stupid. Agreed this was just plain loperamide (no nano particles etc to get through the BBB) but still.

Seems more of a dream than a reality. Just hope no one does anything stupid in desperation.
 
Hey vecktor thats very interesting about haloperidol and loperamide also forming dopamine neurotoxins by metabolism.

You can see why no one would have noticed before seeing as antipsychotics are known for causing parkinsonism as a class effect (presumably by a different route), so a bit of extra symptoms from a toxic haloperidol metabolite would be no different from what you might expect anyway. And with loperamide presumably its the benzhydryldimethylamide pharmacophore at the other end that gives such high affinity for PGP so the toxic metabolite also wouldn't penetrate the CNS.

So does this mean that any drug with the 4-phenyl-4-hydroxypiperidine structure will be metabolised to give dopaminergic neurotoxins? Or would substitution on the piperidine ring stop the metabolite forming the same way. Are there any other well known drugs with this structure in apart from haloperidol and loperamide?
 
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