methylphenidate as a lead compound

[vecktor]

Methylphenidate has known abuse potential, particularily if snorted or injected, it is interesting to look at some of the analogues of methylphenidate as potential future stimulants or DOA's, because they have rather been overlooked on this and other forums, especially as they are very easily made.

methylphenidate is a pretty potent DAT NET inhibitor. strange really as it gets into the brain as fast as cocaine, yet is not really euphoric or particularly addictive, which kind of blows the speed of onset theory out of the water.

Some time ago on this forum there was some discussion of 2-benzyl pyridine as an analogue of desoxypipradrol. Another way of looking at this is 2 benzyl piperidine is a methylphenidate minus the carboxylic acid methyl ester.

the 4-chloro phenyl (2-(4-chlorophenylmethyl)piperidine- (chloro on the phenyl part of the benzyl bit) analog and the 3,4 dichlorophenylmethyl- are even more potent
the following are stolen from the paper below and are in order Ki RT55 displacement (so one sort of DAT affinity) nM, DA uptake IC50 nM, NE uptake IC50 nM.
Methiphenidate : 110, 79, 61 nM
Cocaine : 500, 240, 210 (5HT uptake 250) nM
4-chloromethiphenidate: 25, 11, 11 nM
3,4 Dichloromethiphenidate: 1.4, 23, 14 nM

the 3,4 is very potent indeed and what is interesting is the 3,4 dichloro compared to the 4-chloro has much higher DAT affinity, indicated by its very low Ki for RTI55 displacement but it isn't much more effective at inhibiting dopamine uptake, so this indicates that the 3,4 dichloro substitution is good for binding to DAT interfering with the site as RTI 55 (a phenyltropane) uses but that binding in this site does not necessarily cause efficient dopamine uptake blocking. perhaps there are several sites on DAT one of which is better at binding RTI 55 and another which is better at binding Dopamine.
the paper and patent below decsribe replacing the methoxycarbonyl with alkyl groups the most potent being isobutyl which when combined with a 4-chloro gives a compound with an IC50 DA uptake of 5.5 nM 14 times more potent than methiphenidate it is also rather DA selective IC50 NE is 9nM so 2:1 DA over NE. But this compound is slow to get into the brain and long lasting, I also doubt it will be any good for adhd because it has more DA than NE activity and the better ADHD drugs seem to have significant NE activity.

so what does ths mean?

well the substances above still have the methoxycarbonyl so are analogues of methiphenidate, removing this ester group gives 2-benzyl piperidine.
and...
I bet that 2 (4-chloro benzyl) piperidine is active at 5 mg or lower
I bet that 3,4-dichlorobenzyl piperidine is more potent. and that both isomers are active.

I would also bet that 4'4' dichloro desoxypiprardol is active at sub milligram doses.

the 2-(alpha methyl benzyl) piperidine is unknown but the 4 chloro version is described in this paper, and I would expect it to be less potent than methiphenidate and 2-benzyl piperidine.
lenghtenng the alpha methyl to an alpha propyl (alpha propyl benzyl) piperidine should be about 2 times more potent than 2-benzylpyridine. and very long lasting
I think we'll will have to wait a decade or so to find out...

J. Med. Chem., 50 (2), 219 -232, 2007. 10.1021/jm0608614

Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for the Dopamine Transporter

Mark Froimowitz,*

Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.

patent, covers the same material as the article above but is free..

http://www.freepatentsonline.com/20060100243.html

 

[nuke]

Most of my friends agree it's about as addictive as cocaine, however because it's mostly only sold in pills people don't smoke/shoot it and thus it doesn't have as much potential as coke. IV it is highly reinforcing. I've had it oral and intranasal and both ways it never did much for me (same for cocaine, not much in the way of effects with that drug for me). Amphetamines were the only thing that really seemed to have a massive, enjoyable effect on me.

I recall that paper from years ago. When you move to long lasting, slow onset NET and DAT inhibitors you tend to enter into the world of antidepressant drugs, eg bupropion (incidentally another ring-chlorinated compound) or amineptine. With the DAT > NET inhibition you may actually start to get things that can satiate or attenuate addiction, perhaps like disulfiram is for cocaine (a dopamine beta-hydroxylase inhibitor).

I prefer DAT > NET inhibition because it generally seems easier on the body (less vasoconstriction and hypertension) and is more enjoyable. I suspect these may make for anxiolytic drugs, too.

I'm sure it won't be that long before these enter the gray market.

 

[vecktor]

Most of my friends agree it's about as addictive as cocaine, however because it's mostly only sold in pills people don't smoke/shoot it and thus it doesn't have as much potential as coke. IV it is highly reinforcing. I've had it oral and intranasal and both ways it never did much for me (same for cocaine, not much in the way of effects with that drug for me). Amphetamines were the only thing that really seemed to have a massive, enjoyable effect on me.

I recall that paper from years ago. When you move to long lasting, slow onset NET and DAT inhibitors you tend to enter into the world of antidepressant drugs, eg bupropion (incidentally another ring-chlorinated compound) or amineptine. With the DAT > NET inhibition you may actually start to get things that can satiate or attenuate addiction, perhaps like disulfiram is for cocaine (a dopamine beta-hydroxylase inhibitor).

I prefer DAT > NET inhibition because it generally seems easier on the body (less vasoconstriction and hypertension) and is more enjoyable. I suspect these may make for anxiolytic drugs, too.

I'm sure it won't be that long before these enter the gray market.

the thing I took from the 2007 paper above is that the alpha alkyls were slow onset long duration, reading between the lines the chloromethiphenidates were fast onset and potent, which would indicate that the desmethoxycarbonyls ie the 2- benzyl piperidines would also be fast onset.

the other indicators are here with the methiphenidates we have high DAT occupancy and rapid entry in contrast with bupropion ( t-butyl 3-chloro cathinone) the site occupancy is pretty low.

If anyone has a paper giving the numbers for the DAT occupancy of methiphenidate please post here.....

 

[nuke]

the thing I took from the 2007 paper above is that the alpha alkyls were slow onset long duration, reading between the lines the chloromethiphenidates were fast onset and potent, which would indicate that the desmethoxycarbonyls ie the 2- benzyl piperidines would also be fast onset.

the other indicators are here with the methiphenidates we have high DAT occupancy and rapid entry in contrast with bupropion ( t-butyl 3-chloro cathinone) the site occupancy is pretty low.

If anyone has a paper giving the numbers for the DAT occupancy of methiphenidate please post here.....

Ah, sorry, there was an even older paper with reference to 3,4-dichloromethylphenidate that I recall from ages ago..

here's the binding data for methylphenidate + analogues
http://en.wikipedia.org/wiki/User:Nuklear/Phenidate

 

[fastandbulbous]

There's an Israeli paper* that looked at the SAR of reuptake inhibitors in terms of a pharmacophore; this included transportable inhibitors (eg amphetamine) & non-transportable ones (like methylphenidate & pipradrol). It examines the conformation of the drugs when bound to the membrane transporter and relates that to activity.

From that paper, it would appear that 2-benzylpiperidine & it's ring substituted derivatives would be effective DAT & NET inhibitors. Studies using the 4 isomers of methylphenidate allowed for the model to be refined much further. Along with the reference in another paper (can't remember which one but will search) citing 2-benzylpiperidine as being as active a reuptake inhibitor of the two catecholamines as d-amphetamine, it would seem that the p-choro derivative would be active at under 5mg (wonder if being a non transportable substrate prevents the neurotoxicity seen with p-chloroamphetamine?)

* - R.A. Al'tshuler. Khimiko-Farmatsevticheskii Zhurnal, vol 39, no4, pp3-9 (hope your Hebrew is up to scratch! That's where mrs f&b deserves my unending admiration in being fluent in said language )

 

[vecktor]

There's an Israeli paper* that looked at the SAR of reuptake inhibitors in terms of a pharmacophore; this included transportable inhibitors (eg amphetamine) & non-transportable ones (like methylphenidate & pipradrol). It examines the conformation of the drugs when bound to the membrane transporter and relates that to activity.

From that paper, it would appear that 2-benzylpiperidine & it's ring substituted derivatives would be effective DAT & NET inhibitors. Studies using the 4 isomers of methylphenidate allowed for the model to be refined much further. Along with the reference in another paper (can't remember which one but will search) citing 2-benzylpiperidine as being as active a reuptake inhibitor of the two catecholamines as d-amphetamine, it would seem that the p-choro derivative would be active at under 5mg (wonder if being a non transportable substrate prevents the neurotoxicity seen with p-chloroamphetamine?)

* - R.A. Al'tshuler. Khimiko-Farmatsevticheskii Zhurnal, vol 39, no4, pp3-9 (hope your Hebrew is up to scratch! That's where mrs f&b deserves my unending admiration in being fluent in said language )

is this available elctronically anywhere I am coming up with a blank through the normal search engines, the journal doesn't have a website, I am also coming up blank on Author search, Oh Veh!!
does it come in a with pictures format, my hebrew isn't too good
I suppose I had better see if it is one of the russian journals which is translated routinely by turpion or whoever....

as for neurotoxicity isn't PCA transported by SERT and methiphenidates are not good at SERT?

questions questions always with the questions..

v

 

[vecktor]

Ah, sorry, there was an even older paper with reference to 3,4-dichloromethylphenidate that I recall from ages ago..

here's the binding data for methylphenidate + analogues
http://en.wikipedia.org/wiki/User:Nuklear/Phenidate

very cool and a search for user Nuklear on that link and theres some other current stuff,
http://en.wikipedia.org/wiki/User:Nuklear

Nuke- I know you know this but its worth pointing out good info written with a great style far beyond the usual wiki rubbish

 

[kidamnesiac]

the halogens are obvious, but what other substitutions would be worthwhile on the phenyl group? does it need to be electron withdrawing? or would any bulky substituents in the area do the trick? obviously there are some clues already given from the known data but curious how it would play out along the lines of the 4 position in the PEAs

 

[vecktor]

the halogens are obvious, but what other substitutions would be worthwhile on the phenyl group? does it need to be electron withdrawing? or would any bulky substituents in the area do the trick? obviously there are some clues already given from the known data but curious how it would play out along the lines of the 4 position in the PEAs

heres my thoughts:

the suspicion is that it is down to a hydrophobic interaction with another nearby area of DAT which improves the binding of sub optimal (lowish affinity) ligands. therefore whether it is electron donating or withdrawing per se is not so important, a bulky sustituent might do the trick, DAT will tolerate a napthyl replacing the phenyl. then again a short alkyl or other halo like fluoro might also do the trick. 3 and 4 methoxy are not very effective.

the interesting thing about 3,4 dichloro is that it makes the normally less active enantiomer s pretty active, which hooks in neatly with the wrong tropanes (compared to the WIN phenyl tropanes) the benztropine series being potent only when halo substituted, this is a evry strong effect and more powerful than having the wrong stereochemistry elsewhere. DAT affinity though doesn't seem to correlate with DA reuptake activity across different classes of substances which hints again that there are several binding sites on DAT.

V

 

[hussness]

I have to congratulate nuke too on that wiki page. I'll have to start a serious search for a Hebrew translator. How well does fencamfamine fit into this "universal" SAR? (I know I just took that last sentence right out of f&b's mouth!)
Also -- where can I get ahold of that MM2-87 program mentioned on the wiki page? I did a google search and haven't come up with anything substantial.

 

[fastandbulbous]

No need - my other half triumphs again (god she can be smug with it sometimes ) - here's an English translation...

R.A. Al'tshuler, J. Pharm Chem., Vol 39 No4, p169-175 (2005)


I sometimes think I don't deserve her - in both senses of that statement!!

 

[vecktor]

No need - my other half triumphs again (god she can be smug with it sometimes ) - here's an English translation...

R.A. Al'tshuler, J. Pharm Chem., Vol 39 No4, p169-175 (2005)


I sometimes think I don't deserve her - in both senses of that statement!!

brilliant

 

[hussness]

I just got got the article already translated into English. Pm me if you want it.

 

[hussness]

Nuke -- isn't the animated gif on your wiki page the SS isomer? I thought focalin was RR. I'm not trying to be pedantic; I'm just anal about stereochemistry.

 

[toxide]

VEKTOR:
"Some time ago on this forum there was some discussion of 2-benzyl pyridine as an analogue of desoxypipradrol. Another way of looking at this is 2 benzyl piperidine is a methylphenidate minus the carboxylic acid methyl ester."

where was 2benzylPYRIDINE discussed? Is pyridine a suitable replacement for piperidine and pyrrolidine?

 

[vecktor]

VEKTOR:
"Some time ago on this forum there was some discussion of 2-benzyl pyridine as an analogue of desoxypipradrol. Another way of looking at this is 2 benzyl piperidine is a methylphenidate minus the carboxylic acid methyl ester."

where was 2benzylPYRIDINE discussed? Is pyridine a suitable replacement for piperidine and pyrrolidine?

my mistake plain benzyl pyridine was discussed somewhere else here only benzyl piperidine was discussed and I typed pyridine instead of piperidine, 2-benzyl pyridine is to my knowledge inactive.

as for pyridine being a suitable piperidine replacement I would say yes in some cases, for example 4 alpha alpha diphenylmethyl pyridine is a potent DAT inhibitor but it has other problems to do with diabetes.
the 2 benzyl 4-phenyl pyridine is also active as is the isomeric 1,2-diphenyl 1-pyridin-4-yl ethane
worth reading is:
http://www.erowid.org/archive/rhodium/pdf/pyridine.dat-inhibitors.pdf
I have read a couple of the authors other papers and it rather shows the requirements for activity at the DAT and NERT are quite lax.
shering did a lot of work on 3 aryl alkyl pyridines in the late 60's some of which appear rather active.
the pyrrole analogs of some pyrollidines appear active though pyrrole is rather reactive and awkward.
both the pyridines and pyrroles are much less basic than the corresponding piperidines or pyrollidines reducing the water solubility possibly enhancing lipophilicity and therefore access through the BBB.
V

 

[toxide]

hmmm... a,a-diphenyl-4-methanolpyridine is an antipsychotic and has more of an antagonistic effect on dopamine and 2,2-diphenyl-4-piperidinemethanol is also antagonistic would removing the alcohol make them active(or atleast the pyridine)? And what about the replacing the piperidine in desoxypipradrol with pyridine to make 2-2,2-diphenylmethylpyridine(I ask cuz there is access to this one)