That's a different article - the one in question is titled "Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evaluation of the biological activity of MPTP analogs. " and was published in 1989. A request has been posted in the October references thread.

Good find! Truly a nasty family of compounds.

Do you per chance have access to this article?

Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evaluation of the biological activity of MPTP analogs.
S K Youngster, P K Sonsalla, B A Sieber and R E Heikkila
J Pharmacol Exp Ther
June 1989 vol. 249 no. 3 820-828
DOI: Unknown

Abstract: Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and compared to MPTP for their ability to be oxidized by monoamine oxidase (MAO) and for their ability to cause nigrostriatal dopaminergic neurotoxicity in mice. Most of the compounds were oxidized by mouse brain MAO, either predominantly by the B-form or by both the A- and B-forms. The MAO-catalyzed oxidation of all of the MAO substrates resulted in the formation of dihydropyridinium intermediates which, in turn, except for the dihydropyridinium of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, formed pyridinium species as the final oxidation product. Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds.

http://jpet.aspetjournals.org/content/249/3/820.short

Assyl is growing convinced this substance is foolhardy to indulge in and will be compiling all related data and posting a thread to draw attention to the issue.

You are right that those are all N-methyl analogs - but if they explored ones with 4-chloroarenes, the paper may contain useful insight. Importantly, it does not establish other substitutions to be safe, as claimed by EverlastingReign. How could it do so when they were not even explored?

HPP+ has been definitively established to be neurotoxic (haldol metabolite), and does not have a N-methyl substituent. MAO-B is not involved in the transformation, either.

http://www.nature.com/clpt/journal/v77/n2/abs/clpt2005265a.html

Loperamide is known to be neurotoxic, it just doesn't cross the blood brain barrier - and LPP+ is a metabolite of loperamide. Though studies are lacking, it appears highly likely LPP+ is the culprit.

Honestly, it seems the real question is not whether propionylloperamide is neurotoxic, but how acutely neurotoxic it is. Methamphetamine is neurotoxic too, and heavy use has been associated with early onset Parkinson's, but it really isn't severe enough to be cause for alarm for those whose habits remain within reason. Either way, Assyl wouldn't want to be the lab monkey for this one.

There are some of these reverse ester analogs in use in medicine, such as prodine, but they have a 3-methyl on the ring to inhibit metabolism to the toxic pyridinium specicies. Given that many other potent pethidine analogs have been explored, and even marketed, such as phenoperidine, and the reverse esters have consistently been found to be 10-20x more potent, it seems hard to believe they don't carry toxicity issues.

 
Reference Information


Structure-activity study of the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. I. Evaluation of the biological activity of MPTP analogs.
S K Youngster, P K Sonsalla, B A Sieber and R E Heikkila
J Pharmacol Exp Ther
June 1989 vol. 249 no. 3 820-828
DOI: Unknown

Abstract:
Several analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and compared to MPTP for their ability to be oxidized by monoamine oxidase (MAO) and for their ability to cause nigrostriatal dopaminergic neurotoxicity in mice. Most of the compounds were oxidized by mouse brain MAO, either predominantly by the B-form or by both the A- and B-forms. The MAO-catalyzed oxidation of all of the MAO substrates resulted in the formation of dihydropyridinium intermediates which, in turn, except for the dihydropyridinium of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, formed pyridinium species as the final oxidation product. Nine analogs were found to be neurotoxic; all were oxidized by MAO to pyridinium compounds.

Note
Assyl is growing convinced this substance is foolhardy to indulge in and will be compiling all related data and posting a thread to draw attention to the issue.

As a side note, I have mentioned elsewhere that alpha,p-dimethylstyrene can be easily synthesized from citral by oxidizing it using chloranil in the presence of p-toluenesulfonic acid in high yield. Chloranil can be easily produced by treating hydroquinone or benzoquinone with HCl and H2O2. The first reaction is described in a Synth. Commun. paper from the 1980s, the second in a patent, both of which I can provide when I'm back at home tomorrow.

This makes the suggested route awfully OTC. I only wonder how that methyl-group on the aromatic ring will affect overall potency?

we discussed that it would drop potency quite a bit i found that cumene hydroperoxide is easily reduced by sodium bisulfate or even activated c just by passing it over to cumyl alcohol which in turn can be dehydrated.
cumene hydroperoxide is a curing agent in poly styrene fiberglass type resins i'm sure it's used in  industry

ah yes on WD some time ago, I am forgetful at times... but a considerable drop in potency is still worth something with these ultra-potent type compounds?

cumene hydroperoxide is indeed pretty common as the chief product according to several MSDS's of certain industrial products in my region that I've just checked

Pardon me if I'm not fully following the lines of thoughts here, but instead of the N-diester substituent, why not go with N-ß-anilinoethyl-4-phenyl-4-propionoxypiperidine (13,000x pethidine, roughly 1,000x morphine)?

This info was found in one of my all time favorite books: Opioid Analgesics: Chemistry and Receptors, p 238.  I think the citation for this information is 53: J. Am. Chem. Soc. 70, 1820 (1948) & J. Org. Chem. 10, 277 (1945).  I'm not sure which of the two citations would prove more valuable.  Alkylation would be done with N-(2-bromoethyl)aniline or N-(2-bromoethyl)aniline HBr, not sure which would be better.

I am very interested/concerned in the discussed toxicity issues.  I would think this N-substituent would not likely fall into that category but if you think I'm wrong then I'd love to hear why.

These compounds are even closer to the structure of LPTP, lacking only the amide part: http://www.google.com/patents?hl=en&lr=&vid=USPAT6124318.

See also: xaliproden. http://en.wikipedia.org/wiki/Xaliproden

Just curious....In that Janssen paper Jon provided early on in the discussion, what is it about the ammonium hydrogen sulfate salts, that seems to provide many of them with an unusually low ED:50 ?

I believe because the tests using the ammonium hydrogen sulfate salts were conducted by a different laboratory, so it could have been some other factor like different species of rodent, etc. Some of the tests performed by the 'Eddy' lab showed a lower ED50 than Janssen's lab for a given compound even though both used the HCl salt.