Quick DPMP question

[(zonk)]

I see reference to 2-DPMP analogs with pyrrolidine and ethylamine as suitable replacements on the ring. I also see vague references to 1-Benzhydrylpiperazine derivatives as DRIs. Is there any reason to suspect that 1-DiphenylmethylPIPERAZINE would not be just as active in the same respect to the other compounds?

 

[atara]

I guess it would be, but since every piperazine derivative so far tested has been a big fat failure, you're on shaky ground.

 

[dread]

If the piperazine has the benzhydryl in the 1-position (ie. on the nitrogen) it is likely to be an antihistamine. Cyclizine is 1-benzhydryl-4-methyl-piperazine...

The DRI:s you mention have the benzhydryl in the 2-position, next to the nitrogen, making them beta-phenyl-phenethylamines.


For the record, cyclizine is not stimulating at all... but it does get you messed up if you take enough of it.

 

[atara]

Actually, I wonder if 1-diphenylmethylpiperazine might be an NMDA antagonist, since it has that benzylamine-with-a-big-nonpolar-thing-on-the-benzylic-carbon thing going on like the arylcyclohexylamines. That would be interesting.

 

[NackusBaur]

Today I noticed someone has updated the Wiki article on Desoxypipradrol with a new diagram that shows both enantiomers. I was immediately struck by seeing an extra hydrogen atom depicted off the end of a carbon on the piperidine part. The hydrogen is from the Benzhydryl part? Just different styles of drawing molecules I assume.

New:

Old:

Second question: Is it correct to say that Desoxypipradrol is exactly Methylphenidate but with the methyl groups swapped for another phenyl ring? The stability of the resultant piperidine is what gives 2-DMDP it's enymatic resistance? Also is the Methyl group on MPH directly responsible for additional interaction neurotransmitter transport. If not then would it be correct to assume that difference in pharmacological action of MPH and 2-DMDP has mostly to do with MPH's faster elimination and resultant metabolites?

I apologize if my complete lack of knowledge organic chemistry has rendered this an idiotic/ridiculous question. A positive experience with 2-DMDP has me more curious than I'm qualified to be.

 

[MurphyClox]

I was immediately struck by seeing an extra hydrogen atom depicted off the end of a carbon on the piperidine part. The hydrogen is from the Benzhydryl part? Just different styles of drawing molecules I assume.

No, the "extra" hydrogen is not from the benzhydryl-moiety but from the piperidine, where it is actually attached to (Benzhydryl = Ph2CH-). The difference between the 'new' and the 'old' way of depicting this molecule is that in the latter the stereochemistry was not defined, thus not showing into which direction the proton is pointing, while in the former the stereochemistry is defined (...resulting in the 2 shown different structures).
So, you were right when assuming that it is somehow just a different way of drawing the molecule, albeit with a different content of information, too.

Second question: Is it correct to say that Desoxypipradrol is exactly Methylphenidate but with the methyl groups [1] swapped for another phenyl ring? The stability of the resultant piperidine is what gives 2-DMDP it's enymatic resistance? Also is the Methyl group on MPH directly responsible for additional interaction neurotransmitter transport. If not then would it be correct to assume that difference in pharmacological action of MPH and 2-DMDP has mostly to do with MPH's faster elimination and resultant metabolites?[2]

[1] There are no methyl groups in MPH, but just one of them. And the phenyl ring in desoxypipradol replaces not just the methyl-group in MPH, but the whole methyl-ester (i.e. -COOCH3).
[2] Enzymatic 'resistance' is enhanced by this change, yes, as the benzhydryl can't be hydrolyzed like the ester could.
Differences in pharmacological effects stems partly from the different size between these sidechains in MPH resp. 2-DPMP, but mostly from the aforementioned difference in metabolic stability.


Peace! - Murphy

 

[NackusBaur]

[1] There are no methyl groups in MPH, but just one of them. And the phenyl ring in desoxypipradol replaces not just the methyl-group in MPH, but the whole methyl-ester (i.e. -COOCH3).
[2] Enzymatic 'resistance' is enhanced by this change, yes, as the benzhydryl can't be hydrolyzed like the ester could.
Differences in pharmacological effects stems partly from the different size between these sidechains in MPH resp. 2-DPMP, but mostly from the aforementioned difference in metabolic stability.


Peace! - Murphy

EDIT: Thanks for your informative responce! I've spent the last few hours doing some reading and further developing some ideas. I didn't see your post until I posted this. I'll leave these ramblings as is for you enjoyment--nothing more dangerous than an armchair chemist with access to wikipedia and arrogance from having once heard about things like sp^2 orbitals, enthalpy of activation, and valence energies.

2-DPMP

MPH

I've tried to put together a very broad picture of how these work. I'd appreciate knowing how far in the wrong course I've gone.

Just looking at the 2D diagrams of both compounds, the structural similarities are pretty significant. They both are "triangular" shaped with piperidine group attached to the "handle" of a benzyl group. At the third position, Methylphenidate has a methyl acetate group and and Desoxypipradrol has another phenyl ring that with the benzyl forms a Benzhydryl group.

The piperidine group is mainly what is responsible for the pharmacological affects. It is an amine so it has lots of reactive hydrogens that let it interact with lots of things including neurotransmitter transports. The phenyl group are less reactive because ? (more symmetrical/strong carbon bonds/the carbons keep the hydrogen electrons cloister) and basically serves as a vehicle for the piperidine, getting it where it needs to be and keeping it from getting stuck to something.

Desoxypipradrol has that Benzyhdrl group which is relatively stable and offers few handles for enzymes to grab on to. The Methyl acetate group is the right shape and reactivity to allow enzymes to metabolize the MPH. I realize this is vastly simplifying a very complex system, but does the Methyl acetate serve a significant and direct purpose in interacting with the neurotransmitter soup.

Indirectly, does the smaller methyl acetate allow the MPH molecules to go where the bigger 2-DPMP can't? I assume the methyl acetate's biggest function is has to do with how MPH gets metabolized or eliminated. Because of this MPH gets broken into metabolites quickly, which has the effect of transitioning the pharmacology from MPH to that of its metabolites. 2-DPMP doesn't really metabolize or produces inert metabolites and so the result is that the primary affects just kind of slowly diminish, instead of changing in character like MPH.

Desoxypipadrol gradually decreases the number of dopamine and norepinephrime transporters it's inhibiting. Methylphenidate starts with the same basic DA and NE affects, but changes character as it is turns into metabolites that start pushing other neurotransmitter buttons. This would explain why some have described Desoxypipadrol as "smoother" and "cleaner", and why MPH has a reputation as being fickle, a chimera that turns into something unpredictable, whose effects both depends on/and determine a much wider swath of the brain.

 

[nuke]

The piperidine group is mainly what is responsible for the pharmacological affects. It is an amine so it has lots of reactive hydrogens that let it interact with lots of things including neurotransmitter transports. The phenyl group are less reactive because ? (more symmetrical/strong carbon bonds/the carbons keep the hydrogen electrons cloister) and basically serves as a vehicle for the piperidine, getting it where it needs to be and keeping it from getting stuck to something.

The piperidine here is a secondary amine and therefore an excellent hydrogen acceptor as well as hydrogen bonding partner, although I wouldn't describe the hydrogens on it as reactive. The phenyl group is less reactive because of resonance and pi-orbitals, but inside the body enzymes often catalyze reactions with it to add hydroxyl groups eg. amphetamine metabolism.

Desoxypipradrol has that Benzyhdrl group which is relatively stable and offers few handles for enzymes to grab on to. The Methyl acetate group is the right shape and reactivity to allow enzymes to metabolize the MPH. I realize this is vastly simplifying a very complex system, but does the Methyl acetate serve a significant and direct purpose in interacting with the neurotransmitter soup.

Indirectly, does the smaller methyl acetate allow the MPH molecules to go where the bigger 2-DPMP can't? I assume the methyl acetate's biggest function is has to do with how MPH gets metabolized or eliminated. Because of this MPH gets broken into metabolites quickly, which has the effect of transitioning the pharmacology from MPH to that of its metabolites. 2-DPMP doesn't really metabolize or produces inert metabolites and so the result is that the primary affects just kind of slowly diminish, instead of changing in character like MPH.

There is no methyl acetate in MPH. It is the methyl ester of ritalinic acid. DPMP metabolism and pharmacokinetics have not been extensively investigated so far as I know, so it's difficult to say what exactly happens to it in the body or how it's excreted. Desoxypipradrol is more lipophilic, which also probably explains its enhanced potency and duration. What are inert metabolites and how do you know they exist without data? Do you mean inactive metabolits?

Desoxypipadrol gradually decreases the number of dopamine and norepinephrime transporters it's inhibiting. Methylphenidate starts with the same basic DA and NE affects, but changes character as it is turns into metabolites that start pushing other neurotransmitter buttons. This would explain why some have described Desoxypipadrol as "smoother" and "cleaner", and why MPH has a reputation as being fickle, a chimera that turns into something unpredictable, whose effects both depends on/and determine a much wider swath of the brain.

Metabolites of MPH are generally inactive. Desoxypipradrol is a DAT/NET inhibitor resistant to metabolism and excretion, so it last much longer than MPH. MPH is subject to ester cleavage enzymatically to the inactive and easily excreted ritalinic acid. Desoxypipradrol is usually described as being entirely too long and psychosis generating from most of the trip reports. It may be a little "smoother" if it has less of an effect on norepinephrine than does MPH.

You should pick up an organic chemistry textbook.

 

[MurphyClox]

Thanks for your informative responce!

You're much welcome. Just let me clear out some details, if you don't mind...

They both are "triangular" shaped with piperidine group attached to the "handle" of a benzyl group.

Of course did I notice the speech marks ("..."), but I think its still necessary to remind that the 2D-depictions of these molecules have not much in common with their 3-dimensional shape; the correct term would be tetrahedral instead of "triangular".

It is an amine so it has lots of reactive hydrogens that let it interact with lots of things including neurotransmitter transports.

Errr, it got exactly one hydrogen.


Enough so far. Cheers!

- Murphy


P.S. Just saw that Nuke already commented some of the stuff. Thx Ma'am!

 

[(zonk)]

Wow, a bit off topic^. So adding the extra phenyl to BzP completely eliminates DA activity? Both 1- and 2- benzhydrylpiperidines are active as DRIs.

 

[NackusBaur]

I apologize for those other posts, I've ordered an O-chem textbook off amazon. This shit is so fascinating.

One last dumb question. What if you replaced the piperidine functional group with some other better amine functional groups like methylamine or isopropylamine. Super meth?

 

[fastandbulbous]

The piperidine here is a secondary amine and therefore an excellent hydrogen acceptor as well as hydrogen bonding partner, although I wouldn't describe the hydrogens on it as reactive. The phenyl group is less reactive because of resonance and pi-orbitals, but inside the body enzymes often catalyze reactions with it to add hydroxyl groups eg. amphetamine metabolism.


There is no methyl acetate in MPH. It is the methyl ester of ritalinic acid. DPMP metabolism and pharmacokinetics have not been extensively investigated so far as I know, so it's difficult to say what exactly happens to it in the body or how it's excreted. Desoxypipradrol is more lipophilic, which also probably explains its enhanced potency and duration. What are inert metabolites and how do you know they exist without data? Do you mean inactive metabolits?



Metabolites of MPH are generally inactive. Desoxypipradrol is a DAT/NET inhibitor resistant to metabolism and excretion, so it last much longer than MPH. MPH is subject to ester cleavage enzymatically to the inactive and easily excreted ritalinic acid. Desoxypipradrol is usually described as being entirely too long and psychosis generating from most of the trip reports. It may be a little "smoother" if it has less of an effect on norepinephrine than does MPH.

You should pick up an organic chemistry textbook.

The 'uber-drug' of the series is actually the one where one of the ophenyl groups is replaced by a propyl group - about the same sort of length as the methoxycarbonyl of methylphenidate, but doesn't offer a good enzymematic target - too non-polar. I reckon a methoxymethyl group (or even an ethoxy) might just give the right mix of metabolic availability vs potency (but then I'm rather intoxicated at the minute and rather given to rambling...)

 

[(zonk)]

If 2-benzylpiperidine is somehow(I'm not exactly sure how)analogous to both amphetamine and 1-Benzylpiperazine (again I know the nitrogens are in different position but I always thought after hearing Shulgin mention this that the 1-benzyl/phenylpiperazines were SORTA amphetamines) desoxy fits over 2-BP in the same way that 1-DPMPZ fits over BZP. Am I missing something here?