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Immodium chemistry...

mad_scientist said:
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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no
heres my understanding though I haven't found any proper paper that discusses the SAR of tetrahydropyridine type DA neurotoxins: so he are my rules which may be very wrong:

There must be alkyl or substituted alkyl on the 1 position, those substances without alkyl substitution on the nitrogen are not neurotoxins

the 4 hydroxy must be labile, and subject to elimination, so reversed esters are handy
(gets you to the tetrahydropyridine)

AND

the piperidine ring must be either unsusbstituted or substituted in a way that stabilises the next intermediate oxidised form, the dihydropyridine form, 2 double bonds in the pyridine. phenyl on the 4 position is good because of the resonance stabilisation of the dihydropyridine entity. so possibly alkyl at 3 carboxyl at 2 etc will prevent the stabilisation. the reason why I believe the stabilisation to be important is that 4-benzyl-1-methyl tetrahydropyridine is not neurotoxic, the 4 benzyl doesn't stabilse the intermediate dihydropyridine. substitution on the phenyl ring doesn't seem to be important.
similarly moving the phenyl to the 3 position or even the alpha position (2)
abolishes neurotoxicity,
the tetrahydropyridine intermediate needs to have the double bond isolated from the nitrogen and its delocalised resonance stabilising effects.

though I would be careful as rats are MPTP proof.
for example if one was designing a neurotoxin much more potent than MPTP then 4-(3,4-dichlorophenyl) N-methyl- THP would be obvious because it has much higher DAT affinity.

ALSO
I believe neurotoxic isoquinolines exist
and there are definately neurotoxic B-carbolines

a more general comment:
In the interests of harm reduction I would like to point out, there are better avenues for budding home cooking junk chemists to explore.

My advice is do not go there!!!!

there is a general overview of mptp and parkinsons at
http://www.sulzerlab.org/pdf_articles/Fahn_NeuroRX_04.pdf

if I find a SAR for the neurotoxins I'll post it
 
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http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=3485197&dopt=Abstract

non-neurotoxic prodines (reverse merpidines)
Synthesis and toxicity toward nigrostriatal dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analogues.

Fries DS, de Vries J, Hazelhoff B, Horn AS.

Six compounds having structural features in common with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and tested in mice for the ability to produce a prolonged decrease in nigrostriatal dopamine (DA) and DA metabolites. The compounds that were prepared and tested include the ester elimination products of the analgetic drugs alpha-prodine and trimeperidine. None of the compounds in this study, except for MPTP, produced significant neurotoxic effects in the mouse model. The study shows that minor changes in the tetrahydropyridine ring of MPTP result in a marked decrease in neurotoxicity.
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if someone can get the full article I'd appreciate it

I think only those things that lead to permanently charged final metabolites that are not cleared from the brain are dangerous.
 
Hey vecktor, I have that article. PM me an email address for me to send it to if you like :) .

The article states that addition of one or more methyl groups on the tetrahydropyridine ring results in no observable loss of striatal DA/HVA/DOPAC content when administered to mice in high doses.
However, additions to the phenyl ring, or N-alkyl analogs, does not attenuate the neurotoxicity.
 
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Does anyone know if the tropane MPTP analogue (3-phenyl-2,3-didehydrotropane) show the same sort of neurotoxicity as MPTP? Just that the ethylene bridge of tropane may prevent the analogue of MPP+ from doing a number on the substanti nigra dompaminergic neurones.

If that's the case then I'm surprised that 3-phenyl-3-propionoxytropane hasn't surfaced as a designer opiate as it's simple to prepare from tropinone and has an equivalent potency to MPPP
 
@mattpsy: i don't think it's that simple. just look at the structure of xaliproden, it is a tetrahydropyridine with a substituted phenyl-ring and an n-substituent, but it's completely devoid of neurotoxic effects.
in contrast it's even neuroprotective/neurotrophic and will soon be marketed for these attributes.
 
Immodium has potential but let's face it the synth process would be extremely hard.
 
I was just wondering if loperamide was freebasable(smokeable) or would it(most likely)break down in heat
 
otb01 said:
Immodium has potential but let's face it the synth process would be extremely hard.
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It would be simpler and more attractive to make methadone from scratch than to mess about with Immodium (tm).
In fact, I'm somewhat surprised we have not yet seen spiridone on the street. OK, a little complex to make, but legal & 200x methadone in potency (the original x1500 estimate has subsequently reduced)

Reference?

'morphine-like activity has been found with substitution upon the nitrogen atom of methadone. A series of 4,4-gem disubstituted piperidinyl analogs have been found to be some 1500 times as potent as methadone, and to be quite a bit longer acting'

Taken from:[6] P. A. J. Janssen and C. A. M. van der Eycken, "The Chemical Anatomy of Potent Morphine-like Analgesics." Drugs Affecting the Central Nervous System, (A. Burger, ed.), Dekker, New York 1968, pp. 25-60.
 
maybe this is a stupid idea, but I've read that taking massive amounts of loperamide may yield some results, perhaps some getting through the bbb, I'm not sure exactly, never tried it. but what if you would take a large enough dose of a peripheral acting antagonist like methylnaltrexone with a huge dose of loperamide and then maybe redose on the methylnaltrexone depending on loperamide's halflife. at least we could try taking overdoses of loperamide and still be able to shit the same day lol.
I did post a question about acetylating loperamide into o-acetyl loperamide a while back: http://www.bluelight.ru/vb/showthread.php?t=227410
I'm sure people who are good at chemistry and had the right equipment could make something useful out of loperamide but it seems loperamide is like a philosophers stone, its easier to turn gold into lead than it is to turn lead into gold
 
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WARNING

^^^read the earlier posts in this thread about loperamide neurotoxicity before trying experiments with it.
If it is neurotoxic in humans as well as rats and pigs you could end up with parkinsons disease.
 
Paregoric Kid said:
maybe this is a stupid idea, but I've read that taking massive amounts of loperamide may yield some results, perhaps some getting through the bbb, I'm not sure exactly, never tried it. but what if you would take a large enough dose of a peripheral acting antagonist like methylnaltrexone with a huge dose of loperamide and then maybe redose on the methylnaltrexone depending on loperamide's halflife. at least we could try taking overdoses of loperamide and still be able to shit the same day lol.
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That sounds like a very dangerous assumption that any toxicity of overdosing on loperamide will be from peripheral and CNS opioid activity. There is an article stating loperamide showed extremely moderate analgesc activity when administered IV but only very close to the LD50 (lethal dose where 50% of subjects or animals die) - How do we know the toxic effects of such high doses were purely from effects that methylnaltrexone would be able to reverse?
 
On a side note: Does anyone know if there are references to people be hypersensitive to loperamide?

Almost like the MSG (glutamate flavour enhancer in crisp etc) - the arguement for it being "SAFE" is it doesn't penetrate the BBB and hence glutamate induced excitotoxicty dosn't occur. However many researchers suggested in some people the BBB is far from perfect, or when run down or low on energy (vitamins or minerals included) this safety net can be bypassed.

I wonder if there are individuals with very low opiate tolerance and faulty (for want of a better word) BBB's that have an effect from standard doses.

^ I guess differentiating this from the placebo effect would be near impossible and the incidence of hypersensitivty would probably be too low to be flagged up in clinical trials.
 
at the normal therapeutic dose as an anti-diarrheal which is quite low i asume this is still not an issue even wit those with BBB integrity issues such as i think may occur in the elderly unless perhaps it is used chronically
 
I've experimented with diphenoxylate which is the same in terms of intended use but has slightly better CNS activity due to better BBB penetration I believe.

I really enjoy it eh! LONGGG lasting, euphoric and relaxing experience. Often lasts up to 16 hours!
 
I have noticed mild opiate effects from taking diphenoxylate, although I have no way of knowing whether or not this was due to placebo.
 
maybe this is a stupid idea, but I've read that taking massive amounts of loperamide may yield some results...
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Like ending up being full of shit =D

Sorry couldn't resist :D

I have noticed mild opiate effects from taking diphenoxylate, although I have no way of knowing whether or not this was due to placebo.
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Nah, diphenoxylate is a mu agonist with 50mg being a full on dose (although not as an analgesic as strangly it's reported to be devoid of analgesic action). I hope that it wasn't through taking Lomotil or other such preparation though as they contain 25ug of atropine with each 2.5mg of diphenoxylate (50mg of diphenoxylate would also mean 0.5mg of atropine - yeuck!)
 
good thing I opened with "maybe this is a stupid idea..." I misunderstood the other posts I thought they were talking about turning loperamide into a new substance (yeah I know o-acetyl loperamide is technically different but) I didn't realize loperamide itself could produce mptp like metabolites.

I never did like piperidine opioids, at least the ones I'm familiar with, most of them it seems there is something horrible associated with them, whether it be a side effect like with demerol (and its metabolites) or a byproduct from synthesis like with MPPP, and diphenoxylate (or at least in the form of lomotil) is just shit lol

off topic, is it true pethidine is a dopamine and norepinephrine reuptake inhibitor? I remember reading somewhere it effected dopamine but maybe it wasn't a reuptake inhibitor. does demerol have a "speedy" effect to it? it is strange but demerol is one of the few opioids available by prescription in the US that I haven't gotten to try, though I hear I'm not missing out on much lol
 
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F&B: 50mg!? Man, that sounds pretty strong. The highest i've been willing to go is 37.5mg. I was well toasted! Lay in bed for over 10 hours just feeling nice with the blankets. Mmmm :)
 
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