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Modifications to loperamide

(zonk)

(zonk)

Bluelighter
Joined
May 24, 2008
Messages
687
I was wondering if some simple reactions could be done to greatly increase it's bioavailability such as acetylating the hydroxy and changing the salt from HCl to a dehydroascorbate to help bypass pgp and carry it across the bbb? My supplier said this might be difficult because it's unstable in it's basic form and I'm not sure if dha is acidic enough in any amount to replace the HCl with basifying 1st. Anyway, would these modifications greatly increase bioavailability and would they be practical as I'm not familiar with it's stabilities?
 
changing counterions will not effect how much makes it past PGP.
 
The topic of getting loperamide past the BBB has been discussed extensively in this forum (1) (2), if you're looking for further reading.
 
Acetoxy groups are readily cleaved, so even if O-acetyl-loperamide isn't affected by P-GP, it would be rapidly converted into plain loperamide which would get pumped right back out of the brain (remember, P-GP isn't truly a "barrier" that prevents molecules from getting through, but rather an active transport that removes foreign substances from inside the cell by spending ATP).

Also, the OH-group in loperamide is a tertiary benzylic alcohol, which I'm pretty sure is much harder to esterify than other alcohols.
 
It's not feasible to attempt such a modification. Methadone, dipipanone and dextromoramide are centrally active opioids structurally related to loperamide in that they all contain the 4-amino-2,2-diphenylbutanoate moiety, methadone and dipipanone are ketones with different amino groups and dextromoramide is an amide and has 4-morpholinyl group. To make loperamide centrally active hydrodehydroxylation and/or hydrodearylation would be necessary. Synthetically such transformations are not feasible on loperamide.
 
Dehydroascorbate is being used as a drug delivery agent to bypass pgp
 
(zonk) said:
Dehydroascorbate is being used as a drug delivery agent to bypass pgp
Click to expand...

Do you have any sources for that?

Apparently you can use dehydroascorbic acid as a pro-drug to get ascorbic acid into the brain - the DHA is actively transported into the brain via the glucose transporter, where it is converted back into regular ascorbic acid.

I don't think this has anything to do with PGP; the reason ascorbic acid cannot pass the BBB is most likely that it is way too polar.
 
polybutylcyanoacrylate increased it even more, this was in reference to coated nanoparticles, not sure if just mixing would still work
 
My theory was it would probably bind as a salt but also to the hydroxy group
 
Getting loperamide into the brain is a really bad idea. ICV loperamide is neurotoxic in animals, Loperamide in animals with incomplete BBB causes organic brain damage.

This is a stupid idea, it unfortunately is a stupid idea that never seems to die, periodically a new bunch of morons have the idea of getting loperamide across the BBB

this is from 11 years ago, and this has been discussed ad nauseum since the days of alt.drugs.chemistry

https://www.bluelight.org/vb/archive/index.php/t-331067.html

boring

there are ways to prodrug it to get it across the BBB but they are fortunately out of reach for the typical immodium genius.
 
1-(1-piperidinyl)-3-phenyl-3-(3,4-methylenedioxyphenyl)-3-carbomethoxy-1-methylpropane.png


LOPERAMIDE PRIME

I Don't Make A Lot Of The Drugs You Do.
I Make A Lot Of The Drugs You Do Better.
 
Damn, if we morons then like umm uhh y are there like published research papers about it and stuff.

I get you're coming from a safety perspective but that's not what I'm talking about
 
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(zonk) said:
My theory was it would probably bind as a salt but also to the hydroxy group
Click to expand...

The article talks about conjugates, i.e. esters or amides, not salts.

As I mentioned, esterifying a tertiary alcohol (let alone having that ester be stable) is easier said than done.

Basically, as bizarre as it sounds to say this, this might be one of the rare cases where even if (and that's a big "IF") you succeeded in your endeavours, it would most likely be safer for you to use freaking fentanyl and its analogues.
 
Yeah I'm reading the link vektor posted about pyridinium metabolites. I knew that people who are addicted to lope experience heart problems after prolonged use but wasnt aware that there were such toxic metabolites. Looks like if 1 wanted to use this not only would bioavailability enhancement be required but also cyp3a4 and dat inhibitors

Now I'm scurd to take plain immodium at recommended dosages dont want no pyrrodium
 
Still interested in the use of dehydroascorbate among other things
 
(zonk) said:
..I knew that people who are addicted to lope experience heart problems after prolonged use but wasnt aware that there were such toxic metabolites...
Click to expand...
Loperamide heart problems are due to the drug itself not its metabolites afaik.. Loperamide is a hERG cardiac channel blockers. At high doses, it induces QT interval prolongation and life-threatening cardiac arrhythmias that could lead to sudden death, cf: Loperamide Induced Life Threatening Ventricular Arrhythmia
 
Reaxys links to dozens of papers and patents and the common theme is that they are all peripheral opiate receptor ligands. Clever people look at the patent first and understand why Janssen chose the product from a vary large QSAR study. There are a stack of quite legal medicines that make extremely good precursors to potent opiate agonists but listing them would be a step in harm increment, not harm reduction.
 
Also i know loperamide is toxic and been talked about ALOT and forgive me if i dont want to sort thru all the posts regarding it either but please dont tell me I'm wasting your time when you're taking the to read thru the thread and post that I'm wasting time when you could simply ignore the thread and let it die or be a good citizen and link my ignorant lazy ass to the necessary info
 
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