Designing a New Drug: Ideas for a Drug Design Project

[dillingerESCplan]

Hey, I'm new to these forums, but I've definitely done plenty of lurking over the years and have found this community to be one of the most knowledgeable communities when it comes to topics on drugs. So I'm a Biology major/Chemistry minor and I taking a Chemistry of Drug Design class in order to get Chemistry credits, and also I feel like it would fit my career choice (disease research). It's a pretty interesting class, and I've learned a lot in it about drugs and how they work in the body. Since it's getting around the end of the semester, I've got a project that counts a significant part of my grade, and I need to do well on it in order to pull out an A.

Before I get started, I'm not asking anyone to do my schoolwork for me, I just know that many people in these forums are very well versed on their pharmacology, and any feedback, ideas, or opinions would be greatly appreciated. Anyways, here's what I have to do.

In this project, I have to make a creative one-page ad aimed at the scientific community for a new drug I've designed from a lead compound in order to improve its administration or lessen a side effect. It must include info on my selected disease, a lead compound, at least one modification and its purpose, and a name and structure of a new drug. I want to have something that really impresses my professor, and I figured this would be the best place to ask.

So since I have ADHD, I thought that it would be an interesting idea to figure out a creative way to modify an ADHD medication, like amphetamine or methylphenidate. An idea I had was something along the lines of figuring out a way to modify one of these drugs into a prodrug, kind of like Vyvanse (lisdexamphetamine). The idea of adding an amino acid to a drug in order to make it last longer and lower its abuse potential is an awesome idea, and I was wondering if anyone knew of methods that have been used on other abusable drugs to lower their abuse potential, or any ideas to make a drug extended release, less side effects, etc.

I'll periodically come on here to post any ideas that I come across and see if there is any feedback. Again I don't want to come across as burdening anyone with my schoolwork, I just would like to see if anyone has any creative ideas or any knowledge in this kind of thing. Thanks in advance!

 

[sekio]

"I'm not asking anyone to do my schoolwork, just do this work for my school?"

Read the patent literature?

 

[dillingerESCplan]

"I'm not asking anyone to do my schoolwork, just do this work for my school?"

Read the patent literature?

I don't mean to come across as trying to get anyone to do my schoolwork. I was looking for something more along the lines of feedback on my ideas I post and some discussion on drug modification in general. I've read up on some of the threads in these forums over the years and I'm impressed with how well some people on here know their pharmacology... I've actually learned quite a lot from previous posts here and plan on reading up on some when I have time. Maybe someone on here also knows about other drugs might know methods that are used to make other abusable drugs into prodrugs and that sort of thing. I plan on throwing in some more specific ideas in fairly soon to discuss (I'm ridiculously overloaded with schoolwork so I have to balance it out a bit), but I figured for now I would go ahead and post a thread up. If this isn't appropriate for this forum, I'll understand if a mod chooses to delete this thread.

I've done some reading on how amphetamine is so easily metabolized in the stomach. An idea I was thinking about was a way to allow it to bypass the stomach in order to go into circulation and be broken down by an enzyme in the blood or liver (similar to how Vyvanse utilizes the covalent bonding of lysine to the amphetamine molecule as a way of reducing abuse potential and allowing a prolonged release of medication). There's also the fact that amphetamine absorption in the stomach is greatly dependent on pH, and that a more basic environment, the freebase form of the drug is more lipid-soluble and is more easily absorbed in the epithelial lining of the stomach. Maybe if there's a way to inhibit the breakdown into salt form, or make it more difficult to break down? Also, there's the possibility of functional group modification in order to increase binding affinities to TAAR1. I'll definitely post up more ideas in the future if this thread is still up.

 

[Shamanism]

Perhaps go the metabolite route similar to lisdex with another material perhaps to circumvent a patent ? Stomach ph probably does increase effects but dont think a proff would be very exited, perhaps an amphetamine with added Q10 would actually be very simple and perhaps better health wise more so than reducing acidity for better absorption. But perhaps that is taken better at night.. but also not much of a jaw dropper as far as your assignment goes. Perhaps a rectal pill?
But hey I'm no student. Good luck with your assignment.

 

[knockout_mice]

Aniracetam is a weak, but well tolerated, virtually non-toxic ampakine nootropic drug. It could be useful for AD(H)D. Sadly, it has a really short half-life. It would be cool if you designed a long-lasting prodrug for aniracetam.

 

[Zeds(NCO2CH2CH3)2]

Lisdexamfetamine is cleaved in the blood by esterases, the blood is rich with these. Amphetamine analogues have been wrung dry, N alkyl sub, aromatic sub, benzylic carbon subs(cathinones)..

I would do another drug to expand your learning, consider possibly pemoline, aminorex, etc these would be excellent.
Zedsdead

 

[DL-ark]

Has anyone tried a beta-methyl amphetamine?

You could call it bamphetamine

 

[serotonin2A]

Has anyone tried a beta-methyl amphetamine?

You could call it bamphetamine

That has already been made.

Based on how amphetamine was named, wouldn't it be more correct to call it "bemphetamine"? The name amphetamine is a contraction of AlphaMethylPHenEThylAMINE.

 

[DL-ark]

That has already been made.

Based on how amphetamine was named, wouldn't it be more correct to call it "bemphetamine"? The name amphetamine is a contraction of AlphaMethylPHenEThylAMINE.

Indeed, but you could also phrase it as

BetamethylAlphaMethylPHenEThylAMINE

Or more accurately

BetaAlphadiMethylPHenEThylAMINE

By the way, do you happen to know what the activity of beta methyl amphetamine is?

 

[serotonin2A]

When he suggested betamethylamphetamine, I was thinking he meant beta-methylphenethylamine, not the alpha,beta dimethylated derivative of PEA. The latter compound is closely related to tranylcypromine.

 

[Dresden]

All the good drugs that are reasonably easy synthetic targets have already probably been discovered by now. Mephedrone, MDPV, aPVP, (N-methyl, N-ethyl)-5/6-AP(D)B, MDAI, the 25-X-NBOMe's and methylone were the last crumbs in the carpet to be discovered. Organic chemistry has been around since the Germans discovered it around 1885. Since then, it has been exhaustively researched.

 

[serotonin2A]

I think most of the pharmaceutical industry would disagree with you. The number of known compounds is only a small percentage of the actual number that is possible, even in the molecular weight range of the compounds that you named. And many of the known compounds have never been screened for biological activity. Even thinking about the examples you listed, there are a large number of modifications that could be made that have never been explored.

 

[Dresden]

I think we've gone over the amphetamines rather well and many of the cathinones too. Those are the ones I am mainly interested in.

 

[SkyblueMolly]

Prolintane?

 

[dillingerESCplan]

Just wanted to let you guys know I didn't abandon yall. I had so many tests and papers due last week... had to stay up two days in a row (with two 90 minute naps) last week to get all of the studying done. It was insane. But now I'm on Thanksgiving break, so I only have to worry about writing a research paper, studying for physics, and working on this project. Thanks for all the feedback! I emailed my professor and asked about what type of lead compound would be best to modify and I won't know her response until probably tomorrow, but for now I have a slightly more narrowed-down idea of what I'm trying to do.

Since amphetamine has already been heavily researched, I think that methylphenidate would be an interesting one to consider. One thing I was wondering... how do drug designers know if the drug works on certain receptors (like dopamine and norepinepherine receptors)? Can they tell by the molecular shape of the drug and the receptor (lock-and-key), or do they rely on actually seeing which receptors show more activation of certain areas of the brain by scanning animals/patients who take the drug? If there's a way to tell if the structure can fit into a certain receptor (like how methylphenidate blocks the DAT), then where could I find that out? I wouldn't want to start figuring out ways to change the structure if I have no idea if it would actually fit into certain receptors.

 

[adder]

I doubt that modifying any of drugs from currently used classes of stimulants may bring up a better alternative for ADHD. If I were you, I would choose a disease for which there aren't too many treatments available at the moment.

Since amphetamine has already been heavily researched, I think that methylphenidate would be an interesting one to consider. One thing I was wondering... how do drug designers know if the drug works on certain receptors (like dopamine and norepinepherine receptors)? Can they tell by the molecular shape of the drug and the receptor (lock-and-key), or do they rely on actually seeing which receptors show more activation of certain areas of the brain by scanning animals/patients who take the drug? If there's a way to tell if the structure can fit into a certain receptor (like how methylphenidate blocks the DAT), then where could I find that out? I wouldn't want to start figuring out ways to change the structure if I have no idea if it would actually fit into certain receptors.

Both methods are actually used. The first one is called ligand-based drug design (it relies on finding a pharmacophore, which is then modified for better affinity and/or selectivity etc.) and the second one is called structure-based drug design (it relies on finding 3D homology models of targets). You also need to look for articles on structure-activity relationship of the class of drugs you're interested in.

BTW, what kind of a Drug Design class is it if they don't teach about all of this? I'm not an expert here but it seems to me these are the basics that you absolutely need to know to be able to move on (also - how ligands can bind to their targets - lipophilic interactions, hydrogen bonding etc.).8)

 

[wezface]

Just wanted to pop in and scold the OP for getting "I want a new drug" by Huey Lewis and the News stuck in my head AGAIN.

thanksafuckinlot

 

[dillingerESCplan]

I doubt that modifying any of drugs from currently used classes of stimulants may bring up a better alternative for ADHD. If I were you, I would choose a disease for which there aren't too many treatments available at the moment.

It does seem like ADHD is one of the trickier ones. I was thinking though that there could be something similar to Vyvanse that could be done with methylphenidate (I'll have to read up on what could be added as a carrier group that would slowly be removed in the body). Surely there's something that could make methylphenidate a prodrug. I've been looking for potential areas on the methylphenidate molecule that could hold a carrier group. I also chose ADHD because it's something that I'm very familiar with (did two long presentations on it in Human Genetics Lab). If it seems like it'll be too difficult though, I might change it to another disease/disorder.

Both methods are actually used. The first one is called ligand-based drug design (it relies on finding a pharmacophore, which is then modified for better affinity and/or selectivity etc.) and the second one is called structure-based drug design (it relies on finding 3D homology models of targets). You also need to look for articles on structure-activity relationship of the class of drugs you're interested in.

BTW, what kind of a Drug Design class is it if they don't teach about all of this? I'm not an expert here but it seems to me these are the basics that you absolutely need to know to be able to move on (also - how ligands can bind to their targets - lipophilic interactions, hydrogen bonding etc.).8)

You're right, we did cover that actually... I should have looked back at my notes first . So I'm guessing amphetamine is methylphenidate's pharmacophore? I'm going to also see the search the structure-activity relationship of methylphenidate and see what I can find.

 

[blueberries]

How about a 2-methoxy group (on the piperidine ring) of MPH? Or a vinyl group on the amine of amp (please send me to wherever this is noted because it has to have been done before!).
You could always have 2/3-methfluoro-amp or n-hydroxy-amp.
Or (I'm having fun with this) another amp attached by the amine! That way you'd get two amphetamines for one, or you could alter one by putting a 4-fluoro onto it and you'd have a semi-entactogenic amphetamine. Or just go the whole hog and attach a 2C to amp by the amine hehehe!

Back to MPH though, how about Allylphenidate or Isopropylphenidate?

Then onto other compounds, well, just have a look through the "Random Molecules" thread, take one and say you did it (just to say I have no cares over whether you take shit from here and publish it as your own, unless, that is, you actually create it and name it as your own. Anyways it would be documented here, so the owner could easily say 'Yeah..that's mine. Stop').

 

[sekio]

N-vinyl amines are not stable, they isomerize to an acetaldehyde imine & hydrolyse to the primary amine and acetaldehyde.