methylphenidate potency vs ethylphenidate potency

[plexx92]

I'll bet the issue of ethylphenidate potency in comparison to methylphenidate potency is a matter of optical purity in the RC market vs the pharmaceutical industry. I'll bet ethylphenidate producers do not give a shit if their supply is contaminated with optical impurities. The other 3 isomers of methylphenidate are known to have undesirable side-effects, but the resolving agents necessary to make optically pure ethylphenidate can run for >100$ a gram. If somebody were to go out of their way to actually make optically pure ethylphenidate, I think they would have a very bright future and give ethylphenidate a very good reputation.

What do you guys think?

 

[Burn it up]

That's true: the preparations of methylphenidate used in pharmaceutics contain only the threo enantiomers, while ethylphenidate sold on the RC scene is, as far as I know, a combination of all of them.

TMP = treo-methylphenidate, the ones used in pharmaceutics:

Compd 	DAT (Ki) 	DA (IC50) 	NET (Ki) 	NE (IC50)
D-TMP 	161 	         23 	        206 	        39
L-TMP 	2250       	1600	        >10K             980
DL-TMP 	121        	20        	51 	        788

Williard, R.; Middaugh, L.; Zhu, H.; Patrick, K. (2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology

This makes me wonder. Qualitatively the effects of ethylphanidate were sort of similar to methylphenidate, but I would chose the latter over the first one without a doubt. Methylphenidate is just a fantastic, intense, fun and short lived stimulant with a sweet comedown, while ethylphenidate is a little bit more jittery and unpredictable, and with a little more physical body load.



Interesting related read: Synthesis and Pharmacology of Ethylphenidate Enantiomers -  The Human Transesterification Metabolite of Methylphenidate and Ethanol (download from http://depositfiles.com/files/2m71z3uaa - wait one minute to start downlaod)

 

[sekio]

I have heard from vendors that they sell the D-threo isomer of ethylphenidate; nobody has confimed this with a polarimeter but i have no reason to doubt it.

FWIW, I recall ethylphenidate is about the same efficacy as a DA reuptake inhibitor, with less efficacy at releasing NE.

 

[plexx92]

I have heard from vendors that they sell the D-threo isomer of ethylphenidate; nobody has confimed this with a polarimeter but i have no reason to doubt it.

FWIW, I recall ethylphenidate is about the same efficacy as a DA reuptake inhibitor, with less efficacy at releasing NE.

If ethylphenidate available on the market is more jittery and unpredictable than pharmaceutical methylphenidate, couldn't that imply that what is being sold as 'd-threo ethylphenidate' has a higher efficacy for releasing norepinephrine than methylphenidate. L-threo and (+/-)ethryo methylphenidate are known to cause 'undesirable side-effects' like anxiety and anorexia. Those side-effects, are similar to the less appealling aspects of ethylphenidate in comparison to the methyl ester. That, in turn, suggests that the undesirable aspects of ethylphenidate are not related to the binding profile of the d-threo isomer but rather are different mixture of optical isomers present in ethylphenidate.

Also, because a vendor says something doesn't make it true.

 

[sekio]

I don't follow?

couldn't that imply that what is being sold as 'd-threo ethylphenidate' has a higher efficacy for releasing norepinephrine than methylphenidate.

No? Norepinephrine release does not automatically imply "tweakiness" nor does dopamine release imply "pleasure". Drugs can have high affinity for DAT compared to NET but that does not make them any less "tweaky"... and anyway, methylphenidate is *more* effective at releasing NE than any isomer of ethylphenidate is?

, suggests that the undesirable aspects of ethylphenidate are not related to the binding profile of the d-threo isomer but rather are different mixture of optical isomers present in ethylphenidate.

No again? It is easy enough to selectively make the single isomer.

ps. the [a]D20 for the active isomer of ethylphenidate is reported as +65.10 (c 1.08, methanol).

 

[Mirthero]

ps. the [a]D20 for the active isomer of ethylphenidate is reported as +65.10 (c 1.08, methanol).

what does this mean ?

and please, could someone briefly explain or link info to understand Ki & IC50 notions ?
thx

 

[sekio]

That's specific optical rotation. Chirally pure substances will rotate plane polarised light a specific angle, which you can measure.

Ki and IC50 are measurements in nanomolar (concentration) which are, basically, the level of a drug needed to kick 50% of some other ligand off a receptor (Ki) or cause 50% activation of the receptor (EC50).

 

[Wowbagger]

I was also curious about the isomer that was typically available. I'm fairly certain the majority of what is being sold is d-threo-EPH. There were reports years back about l-threo-EPH available, and that this was far weaker, subjectively. I'd have to look into the synthesis routes that they would use, but I believe that the synthesis does produce the threo diastereomer, and not the erythro.

A simple polarimeter could be used to test if it's d,l-EPH (zero rotation) or d-EPH (+ rotation). If anyone has a sample, they can do a test using a LCD monitor, polarized sunglasses, DI water, and sugar for reference. I would suspect that people would notice an approximately halved potency using the d,l-threo product compared to the d-threo and this would be reported. I'd also expect the d-threo would tend to crystallize out in larger crystals, which is consistent with some reports on appearance.

As far as the other, inactive, isomers giving rise to undesirable drug side effects I have doubts about that. While d-threo-MPH has been available as a drug, the exact difference in effects produced form the d,l is still not clear. FWIW, I could not tell the difference after accounting for potency differences. The potency of EPH relative to pharmaceutical d,l-threo methylphenidate is largely consistent between literature (binding studies give a clue) and subjective reports, which also suggests to me that it is not contaminated with other isomers.

An aside, since we're talking a bit about EPH chemistry: A major problem about EPH-HCl compared to MPH-HCl is that the ethyl ester in EPH appears to be much easier to hydrolyze than the methyl ester in MPH. Thus, ritalinic acid is produced in significant amounts quite rapidly when consumed. This is almost surely the explanation why EPH is so dramatically caustic to nasal membranes and other tissues (relative to MPH).

ps. the [a]D20 for the active isomer of ethylphenidate is reported as +65.10 (c 1.08, methanol)

what does this mean ?

the specific rotation for d-threo-EPH in methanol. if anyone has a lab polarimeter they could measure this

 

[Mirthero]

I'd also expect the d-threo would tend to crystallize out in larger crystals, which is consistent with some reports on appearance.

Good to know ;-) That explains the two different EPH forms usually sold : powder & cristals, I guess.

An aside, since we're talking a bit about EPH chemistry: A major problem about EPH-HCl compared to MPH-HCl is that the ethyl ester in EPH appears to be much easier to hydrolyze than the methyl ester in MPH. Thus, ritalinic acid is produced in significant amounts quite rapidly when consumed. This is almost surely the explanation why EPH is so dramatically caustic to nasal membranes and other tissues (relative to MPH).

In the name of God, juste drop it !
What do you mean "hydrolyse the ethyl ester in EPH" ?

 

[borega]

Good to know ;-) That explains the two different EPH forms usually sold : powder & cristals, I guess.



In the name of God, juste drop it !
What do you mean "hydrolyse the ethyl ester in EPH" ?

you do know in what subforum you are reading here?! If you do not understand what he is saying and you cant get it with the help of google you may want to ask in a nice way but if I recall correctly this forum is not for basic lvl chemistry ppl.

the /r/drugnerds reddit had a nice and brief document on the matter (atleast in parts of comparrison eph-mph) http://cpnp.org/resource/mhc/2013/12/ethylphenidate-biomarker-designer-drug

 

[atara]

the resolving agents necessary to make optically pure ethylphenidate can run for >100$ a gram.

If the synthesis proceeds through a beta-lactam, only the threo isomers are formed, so expensive chiral auxiliaries aren't necessary unless you want to resolve enantiomers. dl-threo-ethylphenidate is probably as good as anything, but Wiki thinks that the erythro isomers of *phenidates are pressors, which could explain some unwanted vasoconstriction in cheap batches.

 

[Coolwhip]

Compd 	DAT (Ki) 	DA (IC50) 	NET (Ki) 	NE (IC50)
D-TMP 	161 	         23 	        206 	        39
L-TMP 	2250       	1600	        >10K             980
DL-TMP 	121        	20        	51 	        788

Williard, R.; Middaugh, L.; Zhu, H.; Patrick, K. (2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology

Could anyone please explain to me why racemic TMP has lower Ki/IC50 values for DAT/DA/NET than either of the stereospecific isomers? The only value that makes sense intuitively is the IC50 for NE...

 

[endotropic]

Could anyone please explain to me why racemic TMP has lower Ki/IC50 values for DAT/DA/NET than either of the stereospecific isomers? The only value that makes sense intuitively is the IC50 for NE...

mind boggling. Do the authors mention it all in the discussion?

 

[Mirthero]

I think it's beaucause of the metabolism and the in-body stabilty of the different isomers. Or something like that.
I understand that one isomer is more potent than the other one, it's the same for a lot of drugs.

But WHY the racemic mixture is even more potent than the more potent isomer alone ? That's weird.

 

[yoyoman]

I found 4-me-tmp the smoothest one by far. But it was so relaxing good (needed a high dose) it almost seemed better to mix it with something else too jittery. It may just calm it down.

I have yet to try isopropylphenidate but after seeing how SMOOTH 4-me-tmp was, its made me wonder about some others. (4f too jittery/paranoid by itself)

 

[Nagelfar]

But WHY the racemic mixture is even more potent than the more potent isomer alone ? That's weird.

If a mathematical truism is not to explain the issue, I think of how the spirocyclic tropanyl-Δ(2)-isoxazoline compounds are so similar to cocaine in their structure, but by function actually change the conformation of the transporters to accept more of the cocaine molecule without itself having any great affinity to bind as cocaine does. All sorts of possible explanations.