Methylphenidate Versus Cocaine - Significant Structural Difference?

[Stevuke79]

Hi guys,

If I understand correctly, the difference between methylphenidate and cocaine is not in how it operates at the synapse, but in it's lipophilicty and traversal of the blood brain barrier. Assuming I have that right, what is the structural source of that difference?

For instance, if I ask the same question about amphetamine and methamphetamine, the difference is also lipophilicity, and the structural source is the additional methyl group. Is it possible to point to an analogous specific difference between methylphenidate and cocaine which would explain the difference in lipophilicity? Does cocaine have a proverbial "methyl group". LOL

I know the universe doesn't always line up for me to enjoy the simple sound-byte answers that my oddball mind craves,.. but a guy can hope, right? This is my first non-introductory post and I know I'm asking a technical question without the technical background to necessarily realize if I'm even being coherent or if it may be obvious that my facts are all screwed up. If this question makes no sense, sorry.

 

[Trying2Iso]

They sure feel a lot different...

 

[Trying2Iso]

I believe they are both dopamine reuptake inhibitors tho

 

[Stevuke79]

Trying2Iso - definitely. Both reuptake inhibitors. (Technically they're slightly different in that respect; only cocaine is a triple uptake inhibitor.)

But I know there is a different in lipophilicity and if I'm not mistaken that accounts for most of the difference (as it does between meth and adderall). And I enjoy being able to say, "No!! You're wrong, .. Adderall is NOT METH, .. because of the way it traverses the blood brain barrier and results in multiple-thousand fold greater increase in dopamine production, .. which can be attributed to the lipophilicity resulting from the n-methyl group."

And so for cocaine I would like to be able to say something similar like: "No!! You're wrong, .. Ritalin is NOT Cocaine! .. because of the way it traverses the blood brain barrier and results in multiple-thousand fold greater increase in dopamine production, .. which can be attributed to the lipophilicity resulting from the [fill in the blank]."

(Or at the very least I would like to know if my understanding is way off)

 

[endotropic]

I think that's oversimplifying the differences a bit. Meth and adderall also differ because meth is a potent 5-HT releaser where-as d-amph is not. Lipophilicity has an effect on the subjective experience, but it's certainly not the only factor differentiating those drugs.

 

[Stevuke79]

Ah, .. well if I can't validate my understanding, the next best thing is knowing I'm wrong.

I like being able to counter the claim "if you look at the two molecules,.. you can't tell them apart.. very similar" .. with: "well, this difference here is a big deal.. "
I know the real response is that even slight differences change the effects of molecules entirely, .. but that doesn't sound as powerful.
(at least I'm honest about what I'm looking for, right?)

Is there a key difference that a lay person like me might be able to understand? (do I need to give up... or if not give up, go to med school?)

 

[endotropic]

Don't give up! You're in the right place to learn.

I'm by no means an amphetamine expert, but I can tell you a few things about them. You're correct that the n-methyl on methamphetamine increases lipophilicity compared to regular amphetamine. In general increasing lipophilicity makes a drug pass into the brain quicker, which makes the effects more intense. The n-methyl also protects the amphetamine molecule from metabolism, so that's a big reason why meth sticks around so much longer.

The reason we can compare regular amphetamine and meth like that is because they ONLY differ by that one methyl. When you try to compare two drugs with lots of differences between their structure (like cocaine and methylphenidate) it gets much harder to say this effect is because of this methyl, this effect that ring. That's why in general when chemists are trying to understand a molecule they'll synthesize a whole series of related chemicals with structures that only differ at one or two positions. That way they can evaluate each chemical and see how each structural change effects the activity.


If you're interested in general how chemical structure determines psychoactivity then I urge you to pick up a copy of PiHKAL and TiHKAL. Flip through the back and find chemicals that are closely related, then see how their effects/potency/duration differ. That's how I started out at least (although that won't help you any if you're only interested in methylphenidate and cocaine, maybe someone else can jump in for those two).

 

[h3lp]

When acute and repeated Methylphenidate treatments effects on neuronal signaling and neuroplasticity with subcomponents of transcription factors, neuropeptides, and components of second messenger cascades were compared to the molecular effects of cocaine and amphetamine there were differences and similarities.

The similarities included altered transcription factor gene regulation between Methylphenidate and Cocaine/Amphetamine.

The differences which resulted included the expression of opioid peptides and postsynaptic density molecules. The resulting hypothesis drawn from the examination suggested that Methylphinidate has produces less neuroadaptations than Cocaine (hcl etc...) and Amphetamine which would further suggest the reduction of addiction potential in regards to Methylphenidate's neuronal transmission in comparison to its less legal counterparts.

Source: http://www.ncbi.nlm.nih.gov/pubmed/17963850

 

[Stevuke79]

Ok cool!! Thank you!!! I just downloaded PiHKAL and TiHKAL from archive.org,... COOL!!!!! Enriching and accessible!! I've to pick up chemistry texts before (wife's old organic chemistry books from undergrad - she's a nurse) .. but I just didn't know where to look for useful information. But flipping through this seems easy enough to understand in my own way and a good place to start.

Heretofore I've been gunning for more quick and "canned" responses .. My favorite one is that the left stereo isomer of meth isn't psycho active but will clear your sinuses. (but the problem is people say, "you can get high on an inhaler!!" .. well yes, but not a vicks levo-meth inhaler. I've tried to come up with a few comparisons that may well be invalid like:
L-Hyoscyamine (treats irritable bowl syndrome) and Ipratropium bromide (treats asthma) are far more similar to cocaine than ritalin.
But to me any tropane alkaloid looks more like Cocaine than a piperidine. I tried to focus on the ones that have other similarities, but seriously what do I know? I know how I've reacted (silently and politely) to a layperson's undeserved air of expertise in my own field so I want to respect the complexity that others work hard to grasp.

Anyway, thanks !!!!

 

[Stevuke79]

Lesson learned: When newbies throw around terms they don't understand people get hurt. Everyone suffers. :D

When acute and repeated Methylphenidate treatments effects on neuronal signaling and neuroplasticity with subcomponents of transcription factors, neuropeptides, and components of second messenger cascades were compared to the molecular effects of cocaine and amphetamine there were differences and similarities.
...
The resulting hypothesis drawn from the examination suggested that Methylphinidate has produces less neuroadaptations than Cocaine (hcl etc...) and Amphetamine which would further suggest the reduction of addiction potential in regards to Methylphenidate's neuronal transmission in comparison to its less legal counterparts. Source: http://www.ncbi.nlm.nih.gov/pubmed/17963850

More seriously, and if I understood what you wrote and the abstract you linked (not sure how likely that is) this is saying that the neurological adaptations from methylphenidate are lesser than those from coke and meth (your brain changes less) ,which implies meth is far less addictive. Awesome! (assuming I got it) This is probably a more "true answer" or more scientific answer to my question. Instead of looking at molecules and hypothesizing about how similar their effects would be, we could just study the question directly. And walla! Someone has!

As an aside, and I say this mostly because I'm laughing at myself, I know that in a world where science and fact are king and queen, this would be all that a person of substance should care about. I'm still compelled by the idea of having some sort of structural argument because the hype is all about the structural similarity and that they're basically the same molecule - so as a lay person talking to lay people, it's nice to just be able to also debunk the false premise.

This was awesome by the way - thank you! I think I vaguely recall hearing about such studies, but not well enough to search for it or even recognize it if it were in front of me. 8)8)

 

[Toz]

Cocaine inhibits 3 transporters (noradrenaline, dopamine and serotonin) at similiar concentrations while methylphenidate inhibits noradrenaline and dopamine transporters 1000x times more effectively than serotonin. That's probably what makes the difference.

source: http://www.biomedcentral.com/1471-2210/6/6

edit: oh this was about structural difference, not difference in effects, sorry my bad

 

[endotropic]

L-Hyoscyamine (treats irritable bowl syndrome) and Ipratropium bromide (treats asthma) are far more similar to cocaine than ritalin.
But to me any tropane alkaloid looks more like Cocaine than a piperidine. I tried to focus on the ones that have other similarities, but seriously what do I know? I know how I've reacted (silently and politely) to a layperson's undeserved air of expertise in my own field so I want to respect the complexity that others work hard to grasp.

Anyway, thanks !!!!
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Yea good examples, isn't chemistry odd?

Look at the structures of morphine and fentanyl:

Almost nothing similar between them, yet they're both very strong opiates (mu opioid receptor agonists to be more precise). Now compare the morphine structure to dextromethorphan, which is basically a mirror image of morphine with a few modifications:

Now there's no opiate activity at all, but it acts as a NMDA receptor blocking dissociative instead! So even though the chemical structures for morphine and dextromethorphan are much more similar, the biological activities of morphine and fentanyl are much more comparable.

One reason its so hard to connect the structures on paper to a biological activity is that these molecules actually exist as flexible 3D objects, we just flatten them out so we can see them better. When they interact with the proteins in our brain it's their folded up shape that's most important, and our flattened out drawings don't show us that shape very well at all. The fact that l-meth and d-meth have such different effects makes a lot more sense when you think about their shapes in 3D space.

 

[Stevuke79]

Actually, that's great. Thank you toz!!

 

[Stevuke79]

Thanks Endotropic. I really appreciate these very detailed answers from everyone. Funny you mention the 3-D structures. When trying to understand this stuff I notice there is a lot I simply have to gloss over (or become a chemist ). I've always been poor at spacial reasoning and since the 3-D models didn't come easy to me I decided they weren't important. LOL!

I think my biggest take away is the basic premise of the books you recommended and understanding that the way drugs are researched is by taking slight variations of similar molecules and simply seeing what happens. It really goes a long way towards conceptually invalidating the aspersions based on the obvious visible similarities between these meds.

Anyway, until I come back for more, thanks everyone!!