In 1976, Barry Kidston, a graduate student from Maryland, synthesized MPPP, a potent reverse ester of pethidine previously reported in the literature. He was apparently unaware of reports of parkinsonian side effects and deaths. Unfortunately, the temperature of the final step of the synthesis was too high and a significant quantity of the eliminated product, MPTP, was produced. He and his friends became known as "The Case of the Frozen Addicts," having developed severe parkinsonian symptoms. Years later, MPTP was identified as a metabolite precursor to MPP+, a pyridinium salt which is uptaken into dopaminergic neurons in the substantia nigra, where it inhibits mitochondrial metabolism, with deadly effects for the cell. DAT inhibitors block this toxicity.
Relevant is the use of haloperidol (Haldol) as an antipsychotic. Tardive dyskinesia is an irreversible and well documented side effect of this medication. It is also a symptom of Parkinson's. Due to the structural similarity of haloperidol to MPPP, the possibility of the formation of a neurotoxic species, HPP+, was investigated and confirmed as a dopaminergic neurotoxin produced in vivo, both by cytochrome P450 isozymes, largely found in the liver, and by MAO-A in the brain [1] (it is not transformed by MAO-B, unlike MPTP). It is less acutely neurotoxic than MPP+, but still capable of devastating results for the patient. It is also a serotonergic neurotoxin. Ultimately, the lesson here is that a N-methyl substitution on the pyridinium species is not essential to neurotoxicity. Also, unlike MPP+, DAT inhibitors do not block this toxicity. [2]
Today, there are "research chemical" vendors peddling MPPP, some of which appears to be free of MPTP when shot through a GCMS. What is unfortunately less known is that the purity of MPPP does not necessarily imply safety. It is difficult to imagine that this substance is not hydrolyzed in the body (cleaving the ester) in some quantity, and transformed by MAO-B or cytochrome P450 isozymes, ultimately resulting in the same problem - MPP+ killing dopaminergic neurons, though the quantity present would of course not be nearly as significant as that resulting from administration of a dirty product. The lack of immediately apparent harm offers a false sense of security, however, as up to 90% of these neurons can be lost before parkinsonian symptoms appear, at which point normal cell death results in the progression of the disease. The user faces the possibility of early onset Parkinson's at an indeterminate point in the future, depending on metabolism, predisposition to the disease, and level of exposure to the neurotoxins in question. [3]
What suggests that there may be some truth to this theory is the development and marketing of prodine (the 3-methyl analog of MPPP) as a pharmaceutical, a fate MPPP never shared - perhaps MPPP was found to be metabolized to MPP+ in unpublished studies. The 3-methyl substituent offers steric interactions that block these transformations.
Loperamide was developed by the same company that developed Haldol, Janssen Pharmaceuticals, while exploring this family of compounds. The purpose of inserting the N,N-dimethylamide moiety was probably to make the compound a good P-glycoprotein substrate to reduce its ability to enter the brain, and the placement of a 4-chloro on the arene para to the piperidine nitrogen to reduce CNS activity. Alternatively, they may have been aware of loperamide's metabolism to LPP+, and the neurotoxicity of this species. A study found that 4-fluoro isomers of MPP+ were considerably less neurotoxic than 3-fluoroanalogs and especially the unsubstituted ones. [4] Unfortunately, the 4-chloro analog was not studied, so this remains highly speculative. And whether they were privy to this knowledge is a question that may never be answered, due to the secretive nature of private drug discovery and design. But it is worth noting the placement of a 4-chloro in haloperidol as well.
Loperamide is known to be neurotoxic in infants, who lack a developed blood brain barrier. LPP+ itself has difficulty entering the brain, unlike MPP+ and HPP+, most likely due to its character as a P-glycoprotein substrate. [5] However, propionylloperamide obviously enters the brain with ease due to anecdotal reports of high activity, and even LPP+ itself may be crossing over in small quantities, given that loperamide does so with doses orders of magnitude higher than those approved by the FDA for therapeutic use, exhibited by anecdotal reports of CNS activity - P-glycoprotein does not catch everything. LPP+ has been found to result from transformation of loperamide by CYP3A4, which again, is largely found in the liver, but has also been found in the brain. [6] Whether loperamide, or propionylloperamide is ultimately transformed by MAO-A to LPP+ in the brain (as is the case with one route for the transformation of haloperidol to HPP+), is an open question, and an important one. The fact that LPP+ is largely filtered by P-glycoprotein does offer a significant safety advantage for propionylloperamide over MPPP, meaning ingestion of the eliminated product is much less likely to have immediately dire results, but more subtle, incremental damage remains a concern. Again, up to 90% of dopaminergic neurons in the substantia nigra can be lost before parkinsonian symptoms appear, so the lack of catastrophic effects in those who have used this substance is no proof of its safety.
In the end, several important questions need to be answered:
-- Is propionylloperamide oxidized to LPP+ in the brain?
-- Is propionylloperamide hydrolyzed and then oxidized to LPP+ in the brain?
-- How acutely neurotoxic is LPP+?
-- Does enough LPP+ cross over into the brain to be a concern with chronic, heavy use?
-- What risk is too great? Methamphetamine is neurotoxic and also associated with early onset Parkinson's, but it is widely considered among users to be "safe enough."
Unless propionylloperamide becomes the next "drug epidemic," the answers may never be known.
1. Attached pdf: "thesis haloperidol is oxidized by MAO-A to HPP+ p191"
2. http://www.springerlink.com/content/x033687j06154l4t/
3. Attached pdf: "The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a technical review of its utility and safety"
4. Attached pdf: "Structure activity study of mechanism of 1-methyl-phenyl-1,2,3,6-Tetrahydropyridine"
5. Attached pdf: "Identification of an N-methyl 4-phenylpyridinium-like metabolite of the antidiarrheal agent loperamide in human liver microsomes - underlying reasons(s) for the lack of neurotoxicity despite the bioactivation event"
6. http://molpharm.aspetjournals.org/content/64/1/42
Relevant is the use of haloperidol (Haldol) as an antipsychotic. Tardive dyskinesia is an irreversible and well documented side effect of this medication. It is also a symptom of Parkinson's. Due to the structural similarity of haloperidol to MPPP, the possibility of the formation of a neurotoxic species, HPP+, was investigated and confirmed as a dopaminergic neurotoxin produced in vivo, both by cytochrome P450 isozymes, largely found in the liver, and by MAO-A in the brain [1] (it is not transformed by MAO-B, unlike MPTP). It is less acutely neurotoxic than MPP+, but still capable of devastating results for the patient. It is also a serotonergic neurotoxin. Ultimately, the lesson here is that a N-methyl substitution on the pyridinium species is not essential to neurotoxicity. Also, unlike MPP+, DAT inhibitors do not block this toxicity. [2]
Today, there are "research chemical" vendors peddling MPPP, some of which appears to be free of MPTP when shot through a GCMS. What is unfortunately less known is that the purity of MPPP does not necessarily imply safety. It is difficult to imagine that this substance is not hydrolyzed in the body (cleaving the ester) in some quantity, and transformed by MAO-B or cytochrome P450 isozymes, ultimately resulting in the same problem - MPP+ killing dopaminergic neurons, though the quantity present would of course not be nearly as significant as that resulting from administration of a dirty product. The lack of immediately apparent harm offers a false sense of security, however, as up to 90% of these neurons can be lost before parkinsonian symptoms appear, at which point normal cell death results in the progression of the disease. The user faces the possibility of early onset Parkinson's at an indeterminate point in the future, depending on metabolism, predisposition to the disease, and level of exposure to the neurotoxins in question. [3]
What suggests that there may be some truth to this theory is the development and marketing of prodine (the 3-methyl analog of MPPP) as a pharmaceutical, a fate MPPP never shared - perhaps MPPP was found to be metabolized to MPP+ in unpublished studies. The 3-methyl substituent offers steric interactions that block these transformations.
Loperamide was developed by the same company that developed Haldol, Janssen Pharmaceuticals, while exploring this family of compounds. The purpose of inserting the N,N-dimethylamide moiety was probably to make the compound a good P-glycoprotein substrate to reduce its ability to enter the brain, and the placement of a 4-chloro on the arene para to the piperidine nitrogen to reduce CNS activity. Alternatively, they may have been aware of loperamide's metabolism to LPP+, and the neurotoxicity of this species. A study found that 4-fluoro isomers of MPP+ were considerably less neurotoxic than 3-fluoroanalogs and especially the unsubstituted ones. [4] Unfortunately, the 4-chloro analog was not studied, so this remains highly speculative. And whether they were privy to this knowledge is a question that may never be answered, due to the secretive nature of private drug discovery and design. But it is worth noting the placement of a 4-chloro in haloperidol as well.
Loperamide is known to be neurotoxic in infants, who lack a developed blood brain barrier. LPP+ itself has difficulty entering the brain, unlike MPP+ and HPP+, most likely due to its character as a P-glycoprotein substrate. [5] However, propionylloperamide obviously enters the brain with ease due to anecdotal reports of high activity, and even LPP+ itself may be crossing over in small quantities, given that loperamide does so with doses orders of magnitude higher than those approved by the FDA for therapeutic use, exhibited by anecdotal reports of CNS activity - P-glycoprotein does not catch everything. LPP+ has been found to result from transformation of loperamide by CYP3A4, which again, is largely found in the liver, but has also been found in the brain. [6] Whether loperamide, or propionylloperamide is ultimately transformed by MAO-A to LPP+ in the brain (as is the case with one route for the transformation of haloperidol to HPP+), is an open question, and an important one. The fact that LPP+ is largely filtered by P-glycoprotein does offer a significant safety advantage for propionylloperamide over MPPP, meaning ingestion of the eliminated product is much less likely to have immediately dire results, but more subtle, incremental damage remains a concern. Again, up to 90% of dopaminergic neurons in the substantia nigra can be lost before parkinsonian symptoms appear, so the lack of catastrophic effects in those who have used this substance is no proof of its safety.
In the end, several important questions need to be answered:
-- Is propionylloperamide oxidized to LPP+ in the brain?
-- Is propionylloperamide hydrolyzed and then oxidized to LPP+ in the brain?
-- How acutely neurotoxic is LPP+?
-- Does enough LPP+ cross over into the brain to be a concern with chronic, heavy use?
-- What risk is too great? Methamphetamine is neurotoxic and also associated with early onset Parkinson's, but it is widely considered among users to be "safe enough."
Unless propionylloperamide becomes the next "drug epidemic," the answers may never be known.
1. Attached pdf: "thesis haloperidol is oxidized by MAO-A to HPP+ p191"
2. http://www.springerlink.com/content/x033687j06154l4t/
3. Attached pdf: "The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a technical review of its utility and safety"
4. Attached pdf: "Structure activity study of mechanism of 1-methyl-phenyl-1,2,3,6-Tetrahydropyridine"
5. Attached pdf: "Identification of an N-methyl 4-phenylpyridinium-like metabolite of the antidiarrheal agent loperamide in human liver microsomes - underlying reasons(s) for the lack of neurotoxicity despite the bioactivation event"
6. http://molpharm.aspetjournals.org/content/64/1/42
thesis haloperidol is oxidized by MAO-A to HPP+ p191