Author Topic: alpha-benzylpiperidine & alpha-piperonylpiperidine  (Read 6104 times)

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cattleprodder

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wow, this is getting interesting.
« Reply #20 on: September 11, 2004, 02:33:00 AM »
scarmani, excellent and informative post!!!

Nicodem, sorry for my shoddy adaptation of a part of the synthesis for DOAM found in _PiHKAL_ to a totally different compound.  I don't really have easy access to many journals where I live now, but all these piperidyl stimulants have really peaked mine, and I hope yours and some other peoples', interest.

In particular, scarmani's mention of phacetoperane (phenyl-2-piperidylmethanol) caught my eye.  Although I know I am risking sounding like the village chemistry idiot for not knowing the answer to this simple question already, I'm going to ask it anyway:

Structurally (pseudo)ephedrine is to methamphetamine as phacetoperane is to 2-benzylpiperidine.  Namely, the removal of the benzylic hydroxyl group of each of the former compounds leads to the latter drugs. 

Phacetoperane, while (mildly) controlled in 1st world countries for being a stimulant, is easily obtainable from overseas; a simple Google search showed me this in a matter of minutes. 

Now, here's the big if.  Can commercially available phacetoperane hydrochloride be reduced with red phosphorous and iodine to yield 2-benzylpiperidine (2-BzP)?

I don't see why not, but I am no expert (yet).  ;)

Nicodem, if not, then what article do you need to have looked up for adaptation to a possible 2-BzP synthesis?  I think I could tell from one of your posts, but I want to be sure before trekking over the river and through the woods to the university library and then digging through the ponderous scientific literature for hours on end with no guarantee of finding the article to begin with.  Please be specific if you can.  Thanks.

Scarmani mentions that phacetoperane faces the same limitations as methylphenidate in that only one of its isomers is active.  Well, that is no big deal; just ingest twice as much.  Only one of the isomers of methamphetamine is active, but there are seemingly millions of satisfied tweakers nonetheless, right?  The other negative thing mentioned was the phacetoperane is weaker than Ritalin.  However, upon removal of the hydrophilic -OH group, I have a feeling 2-BzP is going to by VERY active.  This is due to the much more lipophilic properties of 2-BzP compared to phacetoperane.  Again, the comparison to (pseudo)ephedrine and methamphetamine comes to mind, another blood-brain barrier issue.  In that case at the very least, the reduction of the alcohol makes a difference as big as night from day.  Only time will tell, with the help of some chemical and pharmacological pioneering, if I'm right about 2-BzP.  We are the guinea pigs.  Cheers.

The fact that Shulgin first suggested that levophacetoperane might one day become a future drug of abuse only strengthens my resolve to test 2-BzP (which could also be named phenyl-2-piperidylmethane I suppose) for central nervous system activity in humans. 

"Get busy, child!"--The Crystal Method

Nicodem

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Cattleprodder, I'll reply just quickly
« Reply #21 on: September 11, 2004, 05:08:00 AM »
Yes, phacetoperane can be reduced with RB/I method just like ephedrine.
About the activity of 2-benzylpiperidine I know nothing. The reason is that stimulants are not off my interest - that's why I said to check Medline yourself. I don't know exactly what to do with stimulants (except maybe as a study aid).
Anyway, from what I understood phacetoperane is exactly a "desphenyl pipradol" and since pipradol does not act by the same mechanism as (meth)amphetamine I would say that removing the -OH group might not lead to a more potent stimulant. But like I said this is not my area anymore so you should check the difference in activity of pipradol and its deshydroxy analogue. Scarmani should know better on this subject. BTW, that was a great review he prepared. Wish there would be more posts like that one.


cattleprodder

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Nicodem, I agree with your quote that we need...
« Reply #22 on: September 11, 2004, 08:33:00 AM »
Nicodem, I agree with your quote that we need to solve the problem of more and better potential drugs, especially unscheduled ones like 2-piperonylpiperide and 2-benzylpiperidine whose precursors are relatively uncontrolled because they are so obscure.

I'm sorry you don't like stimulants, but I f-ing love them, that's why I'm so excited about stumbling on this seemingly idiot proof synth of 2-benzylpiperidine from commercially available online Chinese phacetoperane hydrochloride, red phosphorous and iodine. 

Rhodium, you have always been my hero(ine), will you be the first to synth and bioassay this easily made stimulant?
I am truly not able, for many reasons.

As for you, Nicodem, I'll leave the challenge of coming up with a synth for 2-piperonylpiperidine in between your time studying for finals.  You are clearly intelligent enough; in fact, you seem like a real chemistry professor to me.  I appreciate your input. 

PLUR (Peace Love Unity Respect) and BURP (Bring Us Real Pills),
the cattleprodder (official Hive gadfly)

longimanus

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some facts and some guesses
« Reply #23 on: September 11, 2004, 11:47:00 AM »
1st - when I said tomorrow I lied (it`s obvious), excuse me. And one of the results I was going to post was 1-phenyl-3-azabicyclo[3.1.0]hexane. Yes, it`s very similar to DOV 21,947. And it`s analgesic; I don`t know what kind of analgesic (narcotic or NSAID or whatever). Further information will be welcomed (read "please, post something!!!").

 cattleprodder - why do you suggest

just ingest twice as much


Just guessing? Let me remind you that there are 2 asymmetric carbon atoms => 4 forms (just like ephedrine, not methamphetamine). But that doesn`t mean that the dose should be 4x, maybe more like 2.342617x.


scarmani

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A few more comments
« Reply #24 on: September 12, 2004, 05:05:00 AM »
Phacetoperane is actually the acetate ester of phenyl-2-piperidinemethanol, but the presumption would be that the ester is metabolically removed.  I think Nicodem might be right -- 2-benzylpiperidine would probably not be more potent relative to phacetoperane; by analogy to pipradol and related compounds, the hydroxyl group seems to increase potency.  However it does seem likely that 2-benzylpiperidine would have activity, although given the simple structure I think it would be mentioned more in the literature if it was anything particularly notable.

As an aside, if anyone is in an adventurous testing mood, 2 and 3 phenyl and benzyl pyrrolidines look directly available without the need for synthesis.

http://forums.lycaeum.org/cgi-bin/ultimatebb.cgi?ubb=get_topic&f=3&t=000984

covers the same line of speculations about 2-benzylpiperazine / 2-benzylpiperidine; gives a few links.

One pipradol-like stimulant subfamily I didn't mention above was:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/diarylpiperidines.txt














Molecule:

1-methyl-4,4-diphenylpiperidine ("CN1CCC(C2=CC=CC=C2)(C3=CC=CC=C3)CC1")



Also just to note that many substituted 4-phenylpiperidines are scheduled as narcotics (opioids) belonging to the pethedine / prodine family.


Sedrick

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A Good Read
« Reply #25 on: September 12, 2004, 02:02:00 PM »
One of the molecules you have drawn is very similar to the structure of Zoloft. That thioindole containing pcp derivative also looked like a fancy heteroaromatic entity. I could see that one being enjoyable.

Fastandbulbous

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A lot more potential stimulants
« Reply #26 on: September 13, 2004, 11:33:00 PM »
First of all, I’d like to correct a mistake in my previous post (as Scarmani did, but I thought I’d best point it out). The 0.5-1mg dosage referred to
3-(alpha,alpha-diphenylmethyl)morpholine  and not 3-benzylmorpholine, which the post implied. I could find no ref. For the dose of 3-benzylmorpholine.

In addition to the excellent post by Scarmani, there are a few additions to the list of active structures. These are all compounds based on the phenethylamine skeleton, and do not cover the phenyltropane groups etc. Most are definitely active (at least as appetite suppressants), but a few stem from a logical extension of known active compounds, using simple measures such as substituting a sulphur atom for an oxygen atom.

In order to arrange them in groups, I have classified them as follows:

2-Benzylpiperidine derivatives
Phenmetrazine derivatives
Alicyclic and oxygen heterocyclics
Other nitrogen heterocyclics.

Most can be found in assorted journals, but a few come from the work I did for my M.Sc. (SAR of anorectic agents), which was included in a larger paper written by a couple of people who had been lecturers during my undergraduate years (I was eventually relegated on said paper to an et al!).

For the names of the following, I have used the approved drug name for compounds that have had some clinical use (because I’m lazy!). Ones marked with an * are ones that should theoretically have activity, but could not be found by searching (a limited number of) journals.

2-Benzylpiperidine derivatives



1 – 2-benzylpiperidine*
2 – methylphenidate
3 – levophacetoperane
4 – pipradrol
5 – alpha,alpha-diphenyl-2-piperidinemethane
6 - alpha,alpha-diphenyl-2-pyrrolidinemethanol
7 - alpha,alpha-diphenyl-2-pyrrolidinemethane
8 - alpha,alpha-diphenyl-3-morpholinemethane
9 – alpha-phenyl-alpha-(2-thienyl)- 2-piperidinemethane*
10- 3-benzylmorpholine*
11- methyl alpha-phenyl-alpha-(3-morpholino)acetate*
12- alpha-phenyl-alpha-(3-morpholino)methanol acetate*

Phenmetrazine derivatives



1 – phenmetrazine
2 – 3,6-dimethyl-2-phenylmorpholine
3 - 3,5-dimethyl-2-phenylmorpholine*
4 – 3-methyl-2-phenylmorpholine-6-one
5 - 3-methyl-2-phenylthiomorpholine*
6 – phenmetramide
7 - 3-methyl-2-(2-thienyl)morpholine*
8 – phendimetrazine
9 – ring substituted phenmetrazine*


Alicyclic and oxygen heterocyclics



1 – fencamfamine
2 – tranylcypromine
3 – 2-phenylcyclopentylamine
4 - 2-phenylcyclohexylamine
5 – 3-amino-2-phenyltetrahydropyran*
6 – 2-aminoindane
7 – 2-aminotetralin
8 – 3-aminochroman*

Other nitrogen heterocyclics



1 – 2-methyl-3-phenylquinuclidine
2 – 2-methyl-3-phenylpiperidine
3 - 2-methyl-3-phenylpyrrolidine*
4 – alpha-(1-pyrrolidyl)propiophenone
5 – prolintane
6 – pyrovalerone
7 – pemoline
8 – aminorex
9 – 4-methylaminorex

As regards the refs., see Scarmani’s comment (but if someone is really interested in one particular compound, I suppose I could make the effort).

If I had to choose one to synth, I would go with one of the morpholine derivative, purely for ease of synthesis. Hope this is of use to someone!

PS - In terms of anorectic activity, compounds that inhibit re-uptake (of dopamine) are far less active than ones stimulating its release (a year of work summed up in a couple of lines - isn't science great!)


scarmani

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1-phenyl-3-azabicyclo[3.1.0]hexane
« Reply #27 on: September 14, 2004, 07:49:00 PM »
> One of the results I was going to post was 1-phenyl-3-azabicyclo[3.1.0]hexane. Yes, it`s very similar to DOV 21,947. And it`s analgesic; I don`t know what kind of analgesic (narcotic or NSAID or whatever). Further information will be welcomed


1-Phenyl-3-azabicyclo[3.1.0]hexane derivatives as new ligands for sigma receptors
Agostino Marrazzo, Andrea Pappalardo, Orazio Prezzavento, Franco Vittorio, and Giuseppe Ronsisvalle,
Arkivoc. Vol 2004(5), 156-169

Abstract:
A series of 1-phenyl-3-azabicyclo[3.1.0]hexanes were synthesized as more conformationally restricted prototypical ó ligands 3-phenylpiperidines with the aim to developing new ó ligands. Compared with 3-phenylpiperidines reported by Largent et al., binding data showed that conformational restriction was not detrimental for ó receptor affinity. Specifically, except for secondary amine 4, all racemic 1-phenyl-3-azabicyclo[3.1.0]hexane derivatives (12-19) showed moderate to high affinity for both ó1 and ó2 receptors. Dextrorotatory isomers with the same configuration of 3-phenylpiperidines to C-1 carbon linked to the phenyl ring showed a better affinity and selectivity for ó1 receptors compared to the respective levorotatory isomers. Compounds (+)-14 and (+)-15 displayed very high affinity for ó1 (Ki = 0.9 and 2.3 nM respectively) but low selectivity for receptor subtypes. Compound (+)-18 with N-phenethyl substituent embodies the highest selectivity for ó1 receptors... Sigma (ó )receptors are typical binding sites interacting with several psychoactive drugs including haloperidol, benzomorphans and phencyclidine.  The ó1 subtype exhibits high affinity for (+)-benzomorphans such as (+)-pentazocine and (+)-N-allylnormetazocine (SKF-10,047) and a reduced affinity for the respective (–)-enantiomers.  Based on animal model studies, this subtype seems to be involved in cocaine induced behavioral changes, in opiate induced analgesia, steroid-induced mental disturbances and alterations in immune functions.

http://www.arkat-usa.org/ark/journal/2004/Tortorella/VT-1017L/1017L.pdf




So, it looks like N-substitution of this structure gives sigma ligands (though apparently not the unsusbtituted molecule).  This might be an explanation for analgesia.  Just as unrelated speculation, sigma affinity could possibly explain the odd effects of

http://www.erowid.org/library/books_online/pihkal/pihkal018.shtml

?  Actually, in this case it might more likely be due to 5-HT1a agonism instead:

http://www.biopsychiatry.com/5ht1apain.htm

.  Who knows.



cattleprodder

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Help me get this straight.
« Reply #28 on: September 17, 2004, 04:05:00 PM »
Fastandbulbous, scarmani, Rhodium or Nicodem,

Is pipradol a stimulant or an analgesic?  Edit:  It's a stimulant.  I'm not suggesting that 2-benzylpiperidine is an analgesic, and thus falls under the SAR umbrella of pipradol as Nicodem suggests, but rather a stimulant under the methamphetamine SAR domain. 

Then again, MDMA is both a stimulant and an analgesic, so who knows?  SARs are largely conjecture and discussions of them often degenerates into different peoples' pure, theoretical and rather pointless speculation (including my own at times). 

In fact, computerized SAR chemistry is one of the biggest failures of modern chemistry as far as I can tell; in fact, when I was still in college they closed the new, multimillion dollar computational chemistry department because it had produced no quality research.

What I'm trying to say is, all this theory is fine, but I just want to actually taste some
2-piperonylpiperidine and 2-benzylpiperidine based on my hunch, which is itself based on cut and paste chemical structure manipulation (the "me too" drug approach in the pharmaceutical world's jargon), that they will have psychoactive properties in common with Ritalin, ecstasy, meth and perhaps be even better.

Until these compounds are made and synthesized and taken either by someone or at least some lab animals, then we will never really know what the acitivity is.  Nicodem suggested that I search medline myself, but according to Fastandbulbous, who has apparently studied this field extensively, such a search would be futile (as he put an asterik by the 2-benzylpiperidine entry in his post, meaning that the compound is expected to have activity but does not show up in the scientific literature). 

However, I do agree with scarmani's statement that if
2-benzylpiperidine were especially active (say, at least as active as methamphetamine), then we would probably know of it by now, but hey, you never know. 

Henry Ford at one time believed that the Model T was such an advanced automobile that it could not be improved on.  However, this attitude leaves no room for scientific advancement because it implies that everything in the world has already been discovered and is known.  I agree that there is nothing new under the Sun and perhaps the amount of knowledge in the universe is in fact infinite, but if that is true, then more has been forgotton over the aeons than has been remembered.

Also, I would like to thank scarmani for pointing out that phacetoperane hydrochloride is actually the acetate ester of 2-piperidinylphenylmethanol.  However, this is only a minor problem because then all one has to do is hydrolyze off the acetate ester with a simple acid or base reflux to get the benzyl alcohol and then reduce the benzylic alcohol with either anhydrous ammonia and lithium or red phosphorous and iodine to yield 2-benzylpiperidine. 

Buying phacetoperane HCl from China and synthesizing
2-benzylpiperidine actually looks easier than making MDMA in many respects.  From what I could tell from a quick online search, phacetoperane is not a controlled substance in the US but may be mildly controlled in Canada and Europe.

The fact that 2-benzylpiperidine (and its methylenedioxy analogue) are seemingly that unexplored and that easy to make, at least in the case of the former anyway, from commercially available and OTC products makes this project very interesting to me. 

That is why I would very much appreciate it, Fastandbulbous, if you could dig up any information you may have or any of your research articles or other information regarding 2-benzylpiperidine or even 2-piperonylpiperidine.  If someone knows how they make phacetoperane commercially I would also be grateful if they would share.  I am interested in knowing the latter synthesis in hopes that it will elucidate a synthetic outline towards 2-piperonylpiperidine, which is one of my ultimate goals.

Even if I don't get any more answers to these questions, this has been an excellent, informative post, you guys.  Thank you for contributing so voluminously.  Scarmani's post alone is almost enough to justify archiving this thread in some way, but that would be of course up to Rhodium.

longimanus,

I meant you would have to eat 2x as much racemic
2-benzylpiperidine, which has only one chiral center and therefore only 2 possible stereoisomers, to get the same effect as eating only x amount of the active stereoisomer of 2-benzylpiperidine.  (Phacetoperane has, as you pointed out, two chiral centers and thus 4 possible stereoisomers, but I wasn't talking about eating that one.)  This crude calculation, as you pointed out, is based on the assumption that one and only one of the stereoisomers retains all psychoactivity and that the other ones have none, an assumption which I am sure is not always the case but seems to be right on target in the case of methamphetamine at least.

scarmani,

I have tried 4-fluoroamphetamine and was not all that impressed.  The florine atom, while very electronegative, is not much bigger than a hydrogen one, so one tends to get better pharmacological results with going up a size to at least a chlorine atom for all of one's designer drug needs.  (For example, 2CI is stronger per gram than 2CB from what I've heard.)  I have a feeling 3,4-difluoroamphetamine would be better than 4-fluoroamphetamine, but I would rather place my bet on 3,4-dichloromethamphetamine, taking an aromatic structural cue from sertraline (Zoloft), which also has a 3,4-dichlorobenzene ring.  The most selective of all the SSRIs, however, is paroxetine (Paxil) and it has the coveted 3,4-methylenedioxybenzene ring system.  Sesamol, the natural product chemical, is actually used to make Paxil I think.

As for 3-methoxy-4-ethoxy(meth)amphetamine, which can definitely be made starting from diethylsulfate and cheap, plentiful, unwatched oil of eugenol, I say GO FOR IT!  I am simplying itching for a real live bee to try this one.  According to Barium, the PEA version of this compound is pleasant and mood elevating.  I still can't figure out why Shulgin never tried 3,4-DMA either, but I guess he had his hands full.

Finally, Nicodem, you mention 3-phenylpyrrolidine.  I know you don't like or at least don't know what to do with stimulants, but do you like tobacco products, because N-methyl-2-(3-pyridinyl)pyrrolidine is none other than nicotine itself? 

How 'bout N-methyl-2-phenylpyrrolidine?  Scarmani intimated a little while ago that these are already commercially available.  Who wants to be the first crackhead to smoke some?  Why did I select N-methyl-2-phenylpyrrolidine?

I know that pyridine is less aromatic when compared to benzene because the lone pair of electrons on the heterocyclic nitrogen are at right angles to the conjugated pi system of the larger ring as a whole. 

Perhaps synthesizing nicotine with a benzene ring instead of a pyridine ring would result in a better (read, more addictive) product or perhaps it would be not fit any of the same receptors anymore without the lost nitrogen and be inactive.  At any rate, I'm going to shut up for now and go smoke a good ole cigarrette and then munch on some more phendimetrazine.

As Shulgin wrote somewhere in _PiHKAL_, "and visions of sugarplums danced in their heads."

MURP (make us real pills)

Nicodem

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Re
« Reply #29 on: September 18, 2004, 02:17:00 AM »
Also, I would like to thank scarmani for pointing out that phacetoperane hydrochloride is actually the acetate ester of 2-piperidinylphenylmethanol.  However, this is only a minor problem because then all one has to do is hydrolyze off the acetate ester with a simple acid or base reflux to get the benzyl alcohol and then reduce the benzylic alcohol with either anhydrous ammonia and lithium or red phosphorous and iodine to yield 2-benzylpiperidine.

If you ever want to use the rP/I method to reduce phacetoperane than I strongly suggest you to leave that acetate ester as it is. Acetates are reduced even faster since the acetoxy group is a much faster leaving group than the hydroxy.

Finally, Nicodem, you mention 3-phenylpyrrolidine.  I know you don't like or at least don't know what to do with stimulants, but do you like tobacco products, because N-methyl-2-(3-pyridinyl)pyrrolidine is none other than nicotine itself?

Nicotine acts at the nicotinic receptors and the pyridine nitrogen is essential in this interaction. Your reasoning makes no sense in neurochemical context. It is even much more far out than, for example, claiming MDMA is psychoactive because it resembles amphetamine. But the contribution of MDMA in dopamine/noradrenaline release is much lower than its contribution in releasing serotonin and inhibiting its uptake. And still here we talk about related neuromodulatory systems while the acetylcholine system is something completely unrelated and is actually a real neurotransmitter system (that is, not just neuromodulatory). If such reasoning would still be actual you would have people claiming that DXM is active because it resembles morphine and other opiates even if it is of the opposite stereochemistry. Yet the interaction of DXM with opiate receptors is negligible.
The only thing that applies here is the key into the lock example. You have to have a key that can accommodate in the lock and certain points on the key that will turn the lock into the wanted position and open or close the door/receptor. It is also important that this key/molecule can pass all the obstacles to come into the contact with the lock/receptor site.

PS: Nicotine is 3-(N-methyl-2-pyrrolidinyl)pyridine and its structure is not much related to the phenyl ring substituted 3-phenylpyrrolidines that I proposed.


cattleprodder

  • Guest
Inductive vs deductive reasoning in med chem
« Reply #30 on: September 18, 2004, 06:29:00 AM »
Nicodem,

Good to hear from you again!  I apologize for misnaming nicotine.  Now let's discuss drug discovery and logic and examine how we think differently about science and drug discovery and what, if anything, that means.

First of all, thank you very much for your advice not to hydrolyze the acetate ester before reducing with red phosphorous and iodine or anhydrous ammonia and lithium.  It is this kind of practical advice that is invaluable to all chemists, and theoretically, the advice also makes sense based on the reaction mechanism and the fact that an acetate ion is a much better leaving group than a hydroxyl moiety. 

Apparently, the total synthesis of 2-benzylpiperidine gets easier every day.  A few days ago we were looking at starting from scratch with benzene, and now the whole scheme seems workable in one step from OTC and internet ordered chems (not that I'm planning anything like that because I'm not).

Second, you are right in that the 3-phenylpyrrolidine that you mention has little to do with nicotine.  If nicotine did not require its pyridine ring in order to maintain its psychoactivity, then my mention of 2-phenylpyrrolidine would have possibly seemed less off the wall from your perspective, or maybe my thinking invariably seems weird when compared with yours--not necessarily a good or bad thing, mind you, just a fact to be noted.

However, now let's debate chemical theory as it relates to drug discovery.  Of course, no matter how one goes about the process, each drug must be isolated and tested for desirable and undesirable side effects.  However, there seem to be two main schools of thought with respect to drug discovery and science and religion too for that matter:  inductive thinkers (who take small bits of information from varied sources and then extrapolate their findings to the big picture) and deductive thinkers (who are the typical rigid scientist type who is detail oriented and does not believe in making connections between and among academic disciplines).  The scientific community prizes detailed, deductive, specific, specialized information and does not try to find patterns in the big picture.  I, however, am an unconventional, inductive thinker and proud of it; I agree with Shulgin when he says that chemistry is an art, and I have more of an artist's temperament than that of a researcher.  Not remarkably, I have had, in the past, trouble in academic and professional settings.  For example, I believe in mythology, astrology, Hinduism, Christianity and science and have no qualms linking astrology to sp2 orbitals if necesssary.

Anyway, here is an example of my "cut and paste the chemical structure approach to drug discovery and understanding." I fully expect conventional thinking scientists like Nicodem to disdain this approach but it sometimes nevertheless holds true.  However, this method was somewhat introduced by Shulgin in the guise of the "try it and see" approach.

It is obvious, as Nicodem has already pointed out, that DXM bears obvious but only distantly related structural resemblence to the poppy based opiates, such as codeine, morphine, hydrocodone and oxycodone.  As an inductive generalist, I therefore would not be overly surprised if dextromethorphan acts on at least some of the known opiate receptors, but probably not a lot of them.  Low and behold, if I recall correctly, DXM acts on the mu (or was it sigma?) opiate receptor to produce its cough suppressing and ketamine like disassociative states, although being only distantly related to the traditional opiates, DXM is not surprisingly a poor pain killer. 

Another synthetic opiate, pentazocine is known to act on the mu or was it sigma? opiate receptor and also produces hallucinations at high doses, yet pentazocine is a much more effective painkiller than DXM (probably not when compared to levorphanol, however). 

One point that I'm getting at is that I agree wholeheartedely with the Transformer I had as a child whose motto as printed on the toy's box said, "Molecular structure is the key to understanding."  I love organic chemistry; it is the only symbolic form of reasoning that connects the tiny to the infinite and can be taylor made to physically create a novel molecule from a preconceived diagram.  I feel the organic chemistry should be taught in high school.  In fact, I feel sorry for people who can't read Kekule chemical drawings.  However, I realize that I am the exception in the modern world of science in that I generalize and inductively reason to the point of connecting astrology to sp2 orbitals.  Also, as a right brained thinker, I can't prove a lot of my ideas and I'm not good at coming up for the reasons I thought of something, but the years of being flamed have paid off, and now I'm proud to be different from the herd.  I realize distinguishing between genius and idiocy can at times be difficult, but bear with me.

Tinkering with the chemical structure methodology has long been used in the pharmaceutical industry.  It works something like this.  One company comes up with a good drug, usually by trial and error, accident or plain good luck.  Next, 20 other companies furiously tinker with the structure until they find a "me too" drug that they can then patent.  This is how we end up with 30 different kinds of benzodiazepines, and that, in my opinion, is a good thing.  I don't know what the first benzodiazepine to be invented was or how it was discovered, but I feel quite sure a computer did not predict jack shit about it.  This is also the process that, starting with penicillin, 2nd, 3rd and 4th generation antibiotics came about.  If this theory of drug discovery is applied to Shulgin's life work then _PiHKAL_ would be a compendium of "me too" drugs based on dopamine (DA), while _TiKHAL_ would be a compendium of drug information based on molecules of the "me too" type of serotonin (5-HT).  DA and 5-HT are arguably the most important neurotransmitters involved with consciousness, so it is not surprising to me that tinkering with them yields interesting results. 

Shulgin, however, is or at least was of the opinion that the mimickry aspect was imaginary or at least unprovable.  However, after experiencing MDMA (a DA mimicker), TMA-2 (a 6-OH-DA mimicker) and TMA-6 (which has in common with DA only the 4-MeO functional group), I can verify that MDMA is the most pleasurable and the other two are marginal at best.  It is on this mimickry aspect that Shulgin's views diverge from mine; this is probably why he never chose to taste 3,4-DMA, while I would predict it to be Ecstasy like.  In the case of psilocin the similarity between it and 5-HT is undeniable.  Another example is GHB and GABA.

For example, according to my theory, I fully believe the reason that MDMA gets you high is that it is shaped like a dopamine molecule made just lipophilic enough to cross the BB barrier and that MDA makes you more likely to hallucinate because DA is implicated in schizophrenia MDA resemembles DA more closely than does MDMA.

Years ago, when perusing my 1996 _Physician's Desk Reference_, I made an interesting observation:  almost all the psychotropic drugs (at least 50 to 60%) had a phenylethylamine skeleton embedded in their structure somewhere or another.  When I look at 2-benzylpiperidine, I see a cross between methamphetamine and methylphenidate (Ritalin) but longer lasting due to the body's relative inability to deaminate the drug.  When I look at the symbol for 2-piperonylpiperidine, I see Ecstasy crossed again with Ritalin.  When I look at morphine and then at MDxx, I see a common
3,4-dioxyphenylethylamino moiety and I realize that narcotic pain pills at times feel a lot like rolling.  I also realize that methamphetamine and MDMA wake you up in a similar fashion and sharing the amphetamine scaffolding.  I could go on (for example, I am willing to wager that you would be amazed at what happens when adding a 3,4-methylenedioxy unit to the phenethylamine portion of fentanyl), for the list is endless (for example, shrooms are just N,N-dimethylated serotonin with the hydroxyl group in a slightly different location), and of course my theory is not always right, but the future of drug abuse may depend on the art of mimickry more than anything else.  Again, to quote Shulgin, psychopharmacology depends on a number of variables such as intuition, chemical skills and luck but not necessarily logic. 

That, I think, is why I love it so.  NOW WOULD SOMEBODY COOK UP SOME 2-benzylpiperidine, 2-piperonylpiperidine, 3-methoxy-4-ethoxy(meth)amphetamine and 3,4-dichloromethamphetamine.  Thanks.

Fastandbulbous

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DXM and opiate receptors
« Reply #31 on: September 20, 2004, 06:44:00 PM »
It is obvious, as Nicodem has already pointed out, that DXM bears obvious but only distantly related structural resemblence to the poppy based opiates

Cattleprodder, although DXM does not show opiate like activity, laevomethorphan and laevorphan are active as classic opiates, the former being equated with codeine and the latter with morphine; in fact, so much so that in the UK they have been listed in the Misuse of Drugs Act. It is merely that the conformation of DXM does not allow it to interact with the mu receptor (I do believe that DXM acts via the one of the sigma receptors).

A couple of other things: I'm sure that 4-chloroamphetamine is quite neurotoxic to serotonogic neurons as are 4-bromo and 4-iodoamphetamine, so 3,4-dichloroamphetamine may well be neurotoxic as well (but I have no data to back that statement up, just a hunch)
Last of all; for all of the dopaminergic drugs that act by stimulaing release of dopamine (as opposed to re-uptake inhibitors), there is a direct correlation between anorectic activity and the drug's CNS stimulant activity, so the better the appetite supressing properties, the higher the abuse potential. The anorectic correlation does not carry over to anorectics that exert their action on serotonogic systems (such as fenfluramine and sibutramine), although when E. Merck first synthed MDMA beck in 1912, they were looking at it for it's appetite supressing activity


cattleprodder

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Phacetoperane, Rimiterol and Pipradol.
« Reply #32 on: September 21, 2004, 01:32:00 AM »
Fastandbulbous,

For some reason, all the 3-only-substituted (3-MeO-amphetamine, Wellbutrin / N-tert-butyl-3-chlorophenylcathinone) or 3,4-disubstituted amphetamines of which I know (MDMA, MDA, MDE, methylone--which I know is strictly speaking a disubstituted methcathinone, and
3,4-DMA) are all very much less toxic than the 4-only-substituted amphetamines (4-MTA, 4-PMA,
4-methylmethamphetamine, and 4-PMMA), perhaps due to MAO inhibition of the latter category combined with stimulating properties as well.  Also, the larger the halogen that is chosen, the more toxic and acute the drug's effects will in general be. 

The order of size in the halogen family is that fluorine is smaller than chlorine is smaller than bromine is smaller than iodine.  Although fluorine is the most electronegative atom in the whole periodic table, its size--comparable to that of a hydrogen atom--severely limits its psychoactive potential.  For example,
4-fluoroamphetamine is very gentle and did not feel neurotoxic to me at all, but it was also weaker than Adderall.

Cl2 is a green gas, but still, I am no more afraid to eat 3,4-dichloroamphetamine than to pop a Zoloft (sertraline HCl), which also shares a 3,4-dichlorobenzene ring to do help it do its dirty work. 

On the other hand, 3,4-dibromoamphetamine I would most likely politely decline if offered any.  Liquid bromine vapors look vile to me and the color is like that of liquified dried blood.  3,4-difluoroamphetamine I will most likely gratefully try should the opportunity present itself, but I only expect it to be slightly better than 4-fluoroamphetamine.

But, back to the topic of this thread, I have all but given up on synthesizing 2-benzylpiperidine from phacetoperane or 2-piperonylpiperidine from Rimiterol due to the severe lack of availability of these precursor chemicals, even from China.

In some countries phacetoperane (the reverse ester of Ritalin/methylphenidate) is outlawed, in others it is prescribed and in the US it is neither outlawed nor prescribed but still hard to find and also conceivably illegal under the Analogue Drug Act as an isomer of Ritalin, a Schedule II drug.  Phacetoperane's dosage (5 to 20 mg per day per person), side effects and indications for use are very similar to Ritalin's.

Pipradol is a Schedule IV drug in the US and therefore must be weak as water.  Rimiterol is a bronchodilator in the UK and as such should not have any desirable, abusable properties to speak of.  However, it can be transformed into 2-piperonylpiperidine with enough effort.  However, doing that would probably not be a very cost effective route either and would be quite laborious.

The lack of availability of these two phenylmethylpiperidines (PMPs) has made me basically declare this project DOA.  I give up, which is a shame, but I doubt that either of them would have bettered either MDMA or methamphetamine, which are both based on natural products as their chief precursors, in the drug desirability department and certainly not in the ease of synthesis competition either.

C'est la vie.

Captain_America

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(Post deleted by Captain_America)
« Reply #33 on: September 21, 2004, 04:00:00 AM »
(empty)

starlight

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cattleprodder
« Reply #34 on: September 21, 2004, 07:47:00 AM »
I have a feeling 3,4-difluoroamphetamine would be better than 4-fluoroamphetamine

It isn't. It is significantly less euphoric than the 4-FA and has a horrible comedown (well, not actually that bad, but horrible given that the effects of the compound are rubbish in the first place). All in all a completely crap drug.

I am no more afraid to eat 3,4-dichloroamphetamine than to pop a Zoloft

Then you must be a fool. One has vastly more clinical data available in humans. You could fry yourself.

Liquid bromine vapors look vile to me and the color is like that of liquified dried blood

That has fuck all to do with neurotoxicity. You ramble.

4-fluoroamphetamine is very gentle

not at 250mg of sulfate salt it isn't/

phenethyl_man

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regarding these hetereocyclics..
« Reply #35 on: September 21, 2004, 09:49:00 PM »
regarding these hetereocyclic compounds; does anyone know if a saturated secondary ring is necessary for activity?  For instance, is there a possibility that a simple and easily synthesized compound such as alpha-(aminomethyl)-naphthalene would be centrally active?

It appears just about everything with this ethylamine modality protruding from an unsubstituted phenyl ring exhibits some type of stimulatory affect; while ring substitutions may produce anything from analgesics and disassociatives to psychedelics.