07-08-02 17:38
No 330141
Check this out, a review on pethidine (& analog chemistry) with a lot of refs.:
http://www.undcp.org/bulletin/bulletin_1
I took a look at the Drug Schedule 1, and what intrigued me were the following molecules:
* MPPP: 1-methyl-4-phenyl-4-propionoxypiperidine
This is a reverse esther of pethidine
* PEPAP: 1-(2-phenylethyl)-4-phenyl-4-acetoxypipe
A problem with the MPPP synthesis is that a neurotoxic by product MPTP can be generated. What is this MPTP? Is it the dehydrogenated alcohol: when PhLi reacts with the N-methyl 4-piperidone, we get a tertiary alcohol, so is MPTP the alkene from this alcohol?
Because of the neurotoxic side product, I think it is not wise to attempt a MPPP synthesis. But what about PEPAP? When PhLi reacts with 1-(phenethyl)-4-piperidone, we get a similar tertiary alcohol. Is the alkene from this alcohol also neurotoxic?
And my last question: Does anyone has some information about PEPAP. It is supposed to be a synthetic narcotic (it's on Schedule 1, so I suppose it would be kind of fun).
How powerfull is it, compared to morphine? What is the ED50?
I would appreciate it if I get some feedback on this.
Thx
(Chief Bee)
07-08-02 19:04
No 330181
MPTP is indeed the alkene, formed by elimination of the alcohol. I don't know if the corresponding N-phenethyl analog is, but I sure wouldn't want to find out personally. Stay away from the entire class just to be sure.
(Old P2P Cook)
07-08-02 19:17
No 330186
we get a tertiary alcohol, so is MPTP the alkene from this alcohol?
MPTP is the alkene formed when the alcohol eliminates water. This occurs during the esterification of the alcohol.
http://www.nih.gov/od/ors/ds/pubs/mptp/
(Hive Bee)
07-09-02 01:26
No 330329
A few years ago I've synthesized the analogs N-Ethyl-4-phenyl-4-propionoxypiperidine and its N-propyl-counterpart. I've performed this synthesis with the commercially available piperidones and phenyllithium. The N-ethyl-analog is much more potent than the N-propyl. To be sure, a GC was made and showed 0.07 percent alkene. PM if you need more info.
(Hive Bee)
07-09-02 04:56
No 330381
Thanks for clarifying this.
Rhodium, I am going to follow your advice. Although the extent of alkene formation is very limited, I guess it is better to be safe than sorry, right?
The synthesis of PEPAP looked very tempting, because I guess the 1-(2-phenethyl)-4-phenyl-4-PROPIONOXYpip
But ... that damned MPTP, arg.
(Old P2P Cook)
07-09-02 22:12
No 330726
Although the extent of alkene formation is very limited, I guess it is better to be safe than sorry, right?
What I have heard is that formation of the alkene is highly sensitive to the reaction conditions during esterification. I wouldn't mess with this class of compounds without good analytical equpment such as HPLC and NMR.
If you search Google for PEPTP you get a number of hits but they all seem to be in German.
http://www.jugend-hilft-jugend.de/suchti
(Hive Bee)
07-09-02 23:50
No 330763
the UK Medicines Control Agency seems to set very tight requirements on the levels of MPTP contamination, well outside the range controllable in non labratory settings. i think fentanyl analogue's would be safer.
For impurity B{MPTP} a limit of not more than 0.1 ppm for Pethidine Hydrochloridefor parenteral use and a limit of not more than 10 ppm for Pethidine Hydrochloride for oral usehad been specified.
source: http://www.mca.gov.uk/aboutagency/regfra
(Hive Bee)
07-10-02 01:56
No 330789
PEPAP is more powerful than the propionoxy derivative, IIRC.
In the older JMC there is an extensive article concerning the analgesic activities of the reversed esters of pethidine. Interestingly, the N-phenylPROPYL-derivatives are more active than the N-phenylethyl. The most active analogue was the N-phenylpropyl-gamma,4-dipropionoxypiper
(Hive Bee)
07-10-02 15:34
No 330986
Nice to know that the phenylpropyl derivatives are more powerfull than the phenylethyl analogs. There exists a drug: phenoperidine, which is the 3-hydroxy-3-phenyl-propyl analog of MPPP. It is 25 - 50 times more powerfull than morphine. The initial dose is 0.02 - 0.1 mg/kg.
Nemo_Tenetur, could you give that ref. of the JMC. Thanks
Blondie, you are right: a fentanyl analog would be safer.
(Hive Bee)
07-12-02 03:51
No 331662
(Rated as: excellent)
P.A.J. Janssen and Nathan B. Eddy:
Compounds related to pethidine-new general chem. methods of increasing the analgesic activity of pethidine
J. Medicinal and Pharmaceutical Chemistry, Vol. 2, No. 1 (1960), page 35 ff.
Dozens of new analogues of pethidine were synthesized and evaluated for its analgesic potency in mice and rats. The replacement of the N-methyl-group by a phenylpropyl or cinnamyl-group (with a double bond) gave very strong analgesics, several hundred times stronger than pethidine (on a molar potency ratio). The most active compound was N-phenylpropyl-gamma,4-dipropionoxy-4-ph
Examples:
N-phenylethyl-4-phenyl-4-acetoxypiperidi
N-phenylethyl-4-phenyl-4-propionoxypiper
N-phenylpropyl-4-phenyl-gamma,4-dipropio
always compared with pethidine.
(Hive Bee)
08-09-02 06:33
No 343470
(Rated as: excellent)
Designer meperidine is sold as SYNTHETIC HEROIN. The primary street analog of meperidine is MPPP (1-methyl-4-phenyl-4-propionpiperidine).
Very specific chemical reaction conditions are required to produce MPPP. In the event of sloppy synthesis, where the pH is too low or the temperature is too high, a contaminant, MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyr
The proposed biochemical mechanism of action of MPTP involves the rapid oxidation of MPTP to MPP+ after systemic administration. This conversion takes place in all tissues studied (brain and systemic), except for the eye, and is necessary for MPTP to exert its toxic effects (Irwin & Langston, 1985). Monoamine oxidase catalyzes this reaction. Highly reactive intermediates may also be formed in the conversion. MPP+ is then taken up by neurons in the substantia nigra where it destroys dopaminergic neurons in this area. Although the formation of MPP+ occurs in many parts of the brain, it remains unclear as to why it selectively accumulates in the substantia nigra and not in other dopaminergic areas of the brain such as the striatum (Langston, 1985). These biochemical mechanisms are undergoing further studies.
MPTP exposure is suspected if the patient answers "yes" to the following questions on initial presentation:
1. Did the pure form of the drug resemble brown sugar?
2. Was there a burning sensation on intravenous injection at the injection site and up through the vein?
3. Was the "high" more "spacey and giddy" than that of heroin?
These questions can help identify MPTP exposures (Latimer, 1985). Other symptoms of MPTP toxicity are discussed below.
Three phases of MPTP toxicity have been identified (Langston, 1985a). The first is an acute phase which occurs on initial exposure to MPTP. Symptoms include disorientation, hallucinations, blurred vision, "nodding off" (a slow downward drifting of the head, and drooping and closure of the eyelids), difficulties in speech and swallowing, intermittent jerking of the limbs, slow movement, and tremor at rest. The second phase is a subacute event which occurs after exposure to the drug.
Two to three days post-exposure there are reports of increased bradykinesia and rigidity of extremities, abrupt onset of "freezing up" and inability to move. Up to three weeks after exposure, awkward posture, progressive slowness of movement and "freezing up" have been reported. Finally, if there is no recovery from the above two phases, a chronic syndrome results.
A permanent Parkinsonian syndrome evolves consisting of classical Parkinsonian symptoms such as bradykinesia, rigidity, resting tremor, fixed stare, and loss of postural reflexes. Recovery from the acute or subacute phase may occur, but it is unlikely once the chronic phase has been reached.
Several mechanisms have been proposed to explain the manifestations of each of the three phases. Possible mechanisms regarding the acute phase include an opiate receptor interaction with MPTP, serotonergic effects of the substance, and a slight dopaminergic deficiency caused by MPTP. Because MPTP is a meperidine analog, an opiate receptor interaction is probably responsible for the "nodding off" which takes place. This phenomenon is typical of exposure to heroin and is due to the same type of opiate receptor interaction. An initial suppression of serotonin in the central nervous system by MPTP is the suggested cause for the hallucinations and retropulsions which occur (Ballard et al, 1985). Motor symptoms are attributed to MPTP's effect on the dopaminergic neurons in the substantia nigra, but the dopamine deficiency is not yet substantial.
The subacute phase is thought to occur once MPTP accumulation reaches a critical threshold before killing cells in the substantia nigra. This theory thus offers an explanation for the delayed onset of symptoms and for the continuation of symptoms after exposure. Metabolic damage, such as impaired dopamine synthesis, is also suggested as a cause of dopamine depletion. Further study of this delayed phase is in progress. The likely cause of the chronic phase is actual nigral cell death. This, in turn, leads to a permanent hypodopaminergic state, and thus permanent Parkinsonism.
Recovery from the acute and subacute phases has two possible explanations. A critical toxic threshold of MPTP may not be reached intracellularly in the substantia nigra, thus the cells can return to normal once exposure is stopped. Or, perhaps less than a critical number of dopaminergic neurons are lost and the remaining cells are able to compensate by overproduction of dopamine, therefore resolving the clinical symptoms.
Typical Parkinsonian treatment modalities are employed in patients who present with MPTP toxicity. Anticholinergic agents only help to reduce the tremor, and thus are of little benefit. CARBIDOPA and LEVODOPA therapy, with or without dopamine agonists, such as BROMOCRIPTINE, are helpful, but complications typical of this therapy have resulted. These problems include dyskinesias, end of dose deterioration, and on-off swings between choreathetosis and Parkinson's symptoms. Studies with monoamine oxidase type B inhibitors, such as PARGYLINE and SELEGILINE, suggest a possible alternative treatment (Tetrud & Langston, 1989; Langston et al, 1984; Fuller & Hemrick-Lueck, 1985). If monoamine oxidase (MAO) is inhibited, the conversion of MPTP to MPP+ is prevented. Thus, MAO inhibitor drugs may provide a protecting effect if given prior to MPTP and may be effective in retarding the progression of symptoms if given after MPTP. Further research is underway concerning drug therapy for MPTP toxicities.
CONCLUSION:
Several significant points can be noted regarding MPTP contamination. First, the risks of designer drugs are great due to the lack of purification after synthesis, the lack of knowledge about what is actually being created, and the presence of possible adulterants. Secondly, MPTP is a very specific neurotoxin which can induce irreversible Parkinson's symptoms at any age. Finally, MPTP administration to laboratory animals, provides scientists an opportunity to study the function of dopamine on the nervous system, the effects of chronic dopamine deficiency, and the effects of chronic dopamine agonist therapy, and other areas of interest. It is hopeful that understanding the mechanisms of MPTP will provide further understanding of Parkinsonism and offer new insights to the understanding and management of this disease.
REFERENCES:
1. Ballard PA, Tetrud JW & Langston JW: Permanent human Parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri
2. Baum RM: New variety of street drugs poses growing problem. Chem Eng 1985; 9:7-16.
3. Fuller RW & Hemrick-Lueck SK: Influence of selective reversible inhibitors of monoamine oxidase on the prolonged depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in mice. Life Sci 1985; 37:1089-1095.
4. Irwin I & Langston JW: Selective accumulation of MPP+ in the substantia nigra: a key to neurotoxicity? Life Sci 1985; 36:207-212.
5. Langston JW: MPTP and Parkinson's disease. Trends in Neurosciences 1985; 8:79-83.
6. Langston JW: MPTP neurotoxicity: an overview and characterization of phases of toxicity. Life Sci 1985a; 36:201-206.
7. Langston JW, Irwin I & Langston EB: Pargyline prevents MPTP induced Parkinsonism in primates. Science 1984; 225(4669):1480-1482.
8. Latimer D: MPTP "brain damage dope" floods west coast suburbs. High Times 1985; 122:19-27.
9. Tetrud JW & Langston JW: The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989; 245:519-522.
(Hive Bee)
08-13-02 05:50
No 345048
MPPP (Methyl-phenyl-propionoxy-piperidin)
PEPAOP (Phen-ethyl-phenyl-acet-oxy-piperidin)
Diese Designer Drogen sind der Wirkung von Heroin so ähnlich, dass sie auch als „synthetische Heroine“ bezeichnet werden. Bei der Synthese bildet sich häufig das hochtoxische Nebenprodukt MPTP (1-Methyl-4-phenyl-1,2,5,6-tetrahydoperi
Insider glauben, mit MPPP die Brücke zwischen Heroin und PCP gefunden zu haben. In reiner Form kommt es zu einem von Heroin ausgelösten identischen Rauschzustand. Ist der Stoff verunreinigt, kommt es zu Parästhesien, Muskelkrämpfen, verzerrter Optik, metallischer Geschmack, Schwitzen, Halluzinationen, Sprachverlust
(Stranger)
09-22-02 01:28
No 359068
Could you mail me the synth on this one
Thank you
(Verbose Viking)
09-22-02 08:34
No 359134
If possible,you should post info like a synthesis for these
substances instead of passing them around through mail/PM.
Also, is MPTP really a problem in the synth?My German is
good enough to make me able to read that,but is it hard
sepearating MPTP from MPPP?
Weedar
My other signature is funny.
(Hive Bee)
09-23-02 08:01
No 359494
Is a dehydration by-product formed during esterifiction with propionc acid and a strong acid esterification catalyst (of the phenyl-methyl-piperidinol), to get the reversed ester, If you use an alternate esterification reaction that does'nt give this dehydration product then you should'nt have any worries.
(Hive Bee)
09-23-02 09:39
No 359520
SPISSHAK, you 're right.
I 've got a little story about MPPP.
It was brought to the market, and after a while the junkies droped like flies: a lot of opioid addicts where rushed to the clinic bacause they had parkinson like symptoms. The dear doctors were rather amazed. And ... it was found out that the clandistine chemist who synthesised tha stuff, was one of those young parkinson patients ...
Serves him right, I dare say.
I don't know about you guys and girlies, but when I buy heroin I would be grrrr... rather angry if the dude cheats me by selling me some synthetic stuff that furthermore contains a neurotoxic side product that screws up the substantia nigra in my brain and gives me irreveversible parkinsonism.
I would be rather angry is an understatement: I would sure as hell get some horses to quarter the dealer.
(Hive Bee)
09-25-02 16:40
No 360541
Slide show concerning MPPP & MPTP:
http://www.chem.vt.edu/chem-dept/office/
Check out slide 4 (whow, parkinsonism in a 23 year old ...) and slide 7. Do you get it now: stay away from this drug.
(Hive Bee)
09-26-02 22:46
No 361129
would an N-ethyl or N-propyl substitution negate this nuerotoxicity found in the by-product?
If I understand correctly if you esterify with acid chloride and use a catalyst like pyridine to keep things basic and promote esterification of the tertiary alcohol via a chloro-propionyl-pyridinyl amide intermediate, This mechanism will suppress the dehydration reaction or even prevent this from happening.
But the question I'd like to have an answer to is whether using a N-substituent besides methyl would yeild a product without such nuerotoxicity.
This is how I learned of the ethyl homolouge being produced in summary.
And it looks to be interesting synthesis.
Sorry, I don´t know about the cyclization mechanism. I´ve synthesized the N-alkyl-4-phenylpiperidin-4-ols from the piperidone (commercially available in Germany) and phenyllithium, followed by esterification with propionylchloride in TBME. This procedure yield directly the desired ester as HCl-salt which is insoluble in TBME (tertiary butyl methyl ether) and can be easy filtered off.
(Note: I'll bet if this is done in pyridine that .07% of the dehydration product 'tetrahydro-phenyl-pyridine' that was mentioned ealier as being analyzed in the product would'nt be found using this to promote esterification .)
and,
The tertiary amine reacts smooth with PhLi, you can recrystallize the piperidin-4-ol intermediate well from light petroleum ether, esterification works also well.
Barring this, is there an efficient way to alpha-ethylstyrene?
How would you build this?
It is not commercially available, and only the alpha-methylstyrene is used in industry.
In the prodine PDF the dehydration product of that compound is said to not suffer from the nuerotoxic effects of it's non-substiuted counterpart.
But the substitution pattern is on the piperidine ring and not on the nitrogen atom.