I have been looking all day and have yet to find it, has anyone found any information on para-chloro Meperidine? That would be a dead give away of activity.

Loperamide is a Meperidine analog not a Fentanyl analog like many assume, if Para-chloro Meperidine is pumped out of the CNS like Loperamide is it would show that the bulky Halogen is the cause of this unusual activity that Loperamide shows.

I honestly am leaning more towards the amide being the #1 cause of why Loperamide is lead out of the CNS by the PGP enzyme but this is all assumptions at the moment.

Haloperidol is also a para-chlorinated phenylpiperidinol, like loperamide, that isn't pumped out of the brain.

Are you sure that it is a PGP substrate? According to http://www.ncbi.nlm.nih.gov/pubmed/17331325 haloperidol is an "inhibitor but not a substrate" of P-glycoprotein.

I do remember jon talking about preparing the ester from the amide, but that it was very short-acting. Maybe jon can elaborate on this.

Are you sure that it is a PGP substrate? According to http://www.ncbi.nlm.nih.gov/pubmed/17331325 haloperidol is an "inhibitor but not a substrate" of P-glycoprotein.

I do remember jon talking about preparing the ester from the amide, but that it was very short-acting. Maybe jon can elaborate on this.

Yes I found a couple fluff pieces about it being a PGP substrate. It seems to inhibit through competitive binding. Just because it binds does not mean its pumped out. In some drugs that is how they get into the brain in the first place.

N-desmethyl-loperamide appears to be the ideal substrate for the PGP leading weight to my hypothesis that this is indeed where the binding occurs the most. When the Nitrogen amide is turned into a ring in the case of the Palifium it does not appear to be taken up by the PGP.

I might attempt hydrolysis of Loperamide but given the small scale I would be working with it would be rather difficult.


http://www.ncbi.nlm.nih.gov/pubmed/20237038

Pitramide is an opioid amide without any N-substituents and which has CNS effects, but of course the amide is on the opposite side of the molecule from the diphenyls.

Yes, very strange.

Note that there is no dehydrated product formed. It's my belief that the larger the N-substituent, the more stable the tertiary alcohol is to dehydration.

just make the ester, it's active
it might be a substrate for pgp but it still gets in the brain maybe because it is more soluble.

Not exactly fun but no doubt active. It did however feel toxic but I want to stress, we DO NOT... want to kill the PGP ability of this as I believe they are the only thing protecting from Loperamides toxic metabolite. This can still be ushered out of the brain though this wonderful transporter instead of staying in the cell destroying it. This is good new and bad news.... It means the toxic effects will not show up right away and will only appear after prolong use as opposed to the frozen addicts case of Demerol analog from hell which had nothing to transport it out and it got stuck showing Parkinson withing days.

I believe the danger in this case is overstated.

First, phenylpropionoxypiperidines bearing an N-substituent (or substitutions on the piperidine ring, such as prodine) are not oxidized by MOA-B, which is the route of activation for the extreme neurotoxin MPTP. See this, for example: http://pubs.acs.org/doi/abs/10.1021/jm00154a002. The only way such molecules can be oxidized to a pyridinium species is by enzymes in the liver. However, such permanently charged molecules are generally excluded from the brain by the blood-brain barrier.

Second, there is no evidence that phenylpiperidinol esters metabolize into the dehydration product, tetrahydropiperidines (at least not in the case of prodine. Source: http://pubs.acs.org/doi/abs/10.1021/jm00277a003), and assuming that they were properly made and not contaminated with the tetrahydropyridine from the get-go.

Compare that with Haloperidol, which contains an unesterified tertiary alcohol and which has been shown to metabolize into significant quantities of the tetrahydropyridine/pyridinium by the liver. These metabolites *may* be responsible for the extrapyrimidal symptoms of Haloperidol that manifest as movement disorders, especially tardive dyskinesia (but typically not Parkinsonism), and these generally take many years of daily use to manifest.

Also, bear in mind that prodine is a reversed ester of pethidine that had been in use for many years with no reported problems associated with neurological damage. In conclusion, I consider this class to be, at most, as safe or safer than haloperidol.