Making Medication for more Dopamine (Experimental for Parkinson’s)
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- Опубліковано 28 вер 2024
- Support my channel with patreon: / chemiolis
In this video I tell the basics behind Parkinson's disease and the currently used classes of medications. I synthesize a new medication of the MAO-B Inhibitor class, with a different structure compared to medication in the same class, that has recently been developed. This new inhibitor, KDS2010, can reversibly bind to the receptor and is very selective, a combination not found in current known MAO-B inhibitors. It seems to be a lot more effective and is currently in long-term trials.
I really enjoy these types of videos where they synthesis actual medications. I find it fascinating.
*synthesise/synthesize 🙂
But yes, it's super fascinating!
*he
"Medication" is a euphemism. In fact, this artificial tri-fluoridated chemical I do not expect to benefit anyone.
@@thomasgarbe8354 that's okay, you are not a medical professional anyway so your opinion on this is irrelevant
@@markdombrovan8849 OP did say "these _types_ of videos", ostensibly referring to multiple channels' creations. Thus, 'they' is appropriate, since there are different creators.
Really love extensive TLC usage in this video. IMHO most powerful analytical tool available to amateur chemist.
Most powerful and most underutilized. I swear 90% of these chemistry channels are just following a recipe and winding up with "high yields" that are probably a bunch of junk because they haven't done any analytics to confirm. Which is crazy because NMR is relatively new as far as chemistry is concerned, and there are lots of great historic techniques that can give really good insight into chemical identification
@@Spencergolde "so after workup i obtained 250 g of this brown junk which i‘m certain is my product in excellent yield and purity, I have no idea why the follow up reaction didn‘t work though“
Finding your channel was such a great moment in my life, I'm not a chemistry student or anything, but I've always been interested in chemistry, especially related to psychoactive drugs and medications. The more advanced technical details go over my head, but I always more or less understand what the procedure is about at the end of your videos. You're exactly what I thought NileRed was aspiring to be some years ago, too bad he's now focusing on making extremely long videos about really basic topics (and well, he lacks the sexy voice of yours OwO)
I do agree. Chemi seems to always be working on something extremely captivating with every video. Each molecule he endeavors to synthesize is always outgoing, peculiar, intriguing, and idiosyncratic. I do wish Nile did similar things more often, but to each their own I guess. His voice is also very soothing and attractive, just like you said, while still commanding your attention naturally. I, too, and not nearly as well versed in organic and inorganic chemistry as Chemi is, but I have amassed enough higher-end general knowledge of chemistry through my pyrotechnics and energetic materials discipline to have a huge passion and appreciation for all things chemistry related. He’s definitely top-tier, and I think he is an invaluable asset to the UA-cam chemists community.
I get so much dopamine whenever theres a new upload
audio visual catalyst for dopamine synthesis
hilarious fvcking group image. lolol
Oopsie!
And that's how the alien pathogens were released, your honor!
Its really amazing to watch this synthesis, my grandfather was heavily effected by PD and sadly passed away a few years ago, it's really amazing to see the progress in new PD treatment, and it has inspired me to study pharmaceutical chemistry. Love the vid, thank you ❤
Parkinsons is caused by neurotoxins. It really is that simple 😊
You should start a series of such pharmaceutical synthesis.
Excellent video! Parkinson's runs in my family so I'm very glad you brought this to my attention
That’s really impressive medicinal chemistry 👏🏼
This (not new) drug made waves in PD research in the 2020-22 year range. According to Neurobiogen's own website, they have yet to get an accepted publication on its efficacy in a PD model. Wierdly enough, it has gained more attention as of 2023 as a "wonder drug" for weight loss/dieting. This makes me suspect that there are issues with side effects at play, but that's only speculation. Anyway, great video as always!
Direct and indirect dopamine agonism (i.e. by limiting its breakdown) is accompanied with nausea. This wouldn't be the first dopaminergic substance marketed for weight loss.
@@Psychx_ That makes sense. I guess what I meant more directly was/wanted to know was: why is this drug's PD relevance seemingly overshadowed by its prospect as a diet pill?
@@qcard76 Because creating a single new drug literally costs billions of USD and failure can happen very late in the development process - even during phase III studies, which are the last hurdle before approval.
It's pretty standard practice to see if a substance can be salvaged to treat another condition if it fails to reach its primary goals but has an otherwise favorable pharmacologic profile (i.e. good resorption, med-long duration of effects, predictable elimination, large therapeutic window, low toxicity).
The most prominent example for such practices are otc sleeping pills containing Benadryl/Diphenhydramine. That substance was developed to treat allergies, and making people sleepy was a side effect.
Nowadays, there are antihistamines that don't cause tiredness anymore and Diphenhydramine is sold as a sleeping aid.
The nausea medicine Metoclopramide is a low-potency antipsychotic btw. and Thalidomide (Contergan) is now used for treating lepropsy, certain cancers and Crohn's disease…
Im not too thrilled about about someone trying to repurpose anything into a diet drug so quickly, and even less thrilled when something is called a wonder drug.
But if it affects how you interact with dopamine, it can have the potential for treating some causes of weight gain.
I'm enjoying your video. I hope, one day, you will have a video about blood pressure-lowering drugs, similar to Lisinipril.
Hey, while youre on MAO inhibitors (and phenethylamines...), make tranylcypromine!! Its a cool molecule, containing a cyclopropane ring that opens in an inactivating reaction with MAO, and a pretty cool synthesis as well, plus its seeing a huge resurgence both as an antidepressant and as a lead compound for epigenetic drugs including cancer treatments
I love your channel. Always something interesting here.
Gotta love how Selegiline is just propargylated meth
Drugs with Fluorine or triple Fluorine have been quite toxic yet there are many big pharma who simply dont care, preferring to focus on the therapeutic effects.
hi ! i used also AcOH glacial and NaBH4 to form a milder reduction agent (AcO)3BHNa , it worked for reductive amination really well , something like 78% yield
Yeah, STABH has very similar reactivity to cyanoborohydride, but it’s a bit more mild. Works well for a lot of reductive animations/alkylations. For people like us who can’t easily get cyanoborohydride (or those who don’t want to work with it) STABH is almost perfect due to its ease of preparation prior to a reduction. The problem with STABH is its extreme sensitivity to water, and protic solvents which limits the solvents that can be used to DCE, DCM, THF, dioxane, toluene, etc. The reactions between STABH, IPA, and EtOH are slower; however, reductions with STABH tend to take long periods of time.
Out of curiosity, what solvent did you use, and how long did you run the reaction?
On another note, sodium monoacetoxyborohydride is apparently able to reduce nitriles and amides to amines which is interesting. Also, there’s a book that has a bunch of info on the capabilities of reducing agents called “Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Agents.” I highly recommend it.
@@ashe1.070 i’m soo enthusiastic that you replied to my comm , thank you ! so , the solvent was AcOH , i used only glacial AcOH and time of reaction was 8h. I did this reaction just to test its efficiency on DMAB as aldehyde and methyl anthranilate as primary aromatic amine( soo strong grape smell 🤢 ) . It was actually a nightmare isolating the product (without acylating the secondary amine with Boc anhydride or other protecting groups propionyl or acetyl ) because it didn t want to precipitate at all , using a pipette I managed to just simply extract the liquid from round bottom flask and just spread it on the entire surface of a petri dish and at room temperature it crystalised out. Very nice crystals , did some Xray and H-NMR and that was about it. For the excess amount of methyl anthranilate , just washed the precipitate with a lot of distilled water and i managed to get rid of the entire excess of amine.
Have a wonderful day and please , keep doing what you’re doing , it’s great !
Always fantastic and so well explained
Love to watch your experiments!
Love the neurobiological background. Find it interesting that some antipsychotic medication, being dopamine and serotonin receptor antagonists can apparently cause parkinson's like symptoms in high doses.
On the topic of serotonin-receptors are you interested in synthesizing some migraine medication like tryptans in the future? ;)
Maybe add the cleanup part
I clicked on this video thinking you were gonna make that one Parkinson's-inducing chemical
As for antiparkinson medications, i always thought amantadine was really interesting. Just for how "simple" it is, a little fragment of diamond (essentially) with an amine stuck on there.
My cynicism is thinking they found a molecule that causes PD while it treats it.
UV TLC was viable for these compounds, easier and faster.
You should try Potassium permanganate as a stain, dip it in and done (wait a bit or heat the plate to 250 °C until you can see the stuff :D)
Your reductive amination mightve not worked because you did not allow time to form the imine. You also need a drop or two of acetic acid to help this along. It's possible your reductant just reduced the aldehyde to the alchol. This is why a weaker reductant is usually used (ie NaCNBH3 over NaBH4)
I read recently that a dose of the BCG vaccine (it’s for tuberculosis) later in life may help fight Alzheimer’s disease.
degasses the PhMe/H2O mixture with N2, then proceeds to charge the reagents in open air...
Takes about 30 minutes for oxygen to fully diffuse back into a solvent, so a few minutes is not bad enough for the lazy ;-)
@ucewillis you‘re not wrong but you‘re also greatly exaggerating the effect of air on the effectiveness of suzuki couplings. It‘s incredible how stable these actually air-sensitive reactions are. Also note that suzuki couplings must have some water in them, 100% anhydrous conditions mean the reaction fails!!
@Chemiolis as long as you keep doing suzuki couplings you don‘t really need to change your procedure. If you ever decide to do a negishi coupling though make sure to use proper Schlenk techniques
@user-zo2ie1ml2d I don't really care sorry mate
@@user-zo2ie1ml2d Why do Negishi when you can use Suzuki, though?
Also, at that point, do a Stille coupling, then.
Stannanes and boronic acids/boronates are easier to handle than organozinc compounds.
Fantastic, i was facsinated by the use of the 1-hydrosilatrane, the endind got me, what a way to lose the product haha
Hi Chemiolis, can you synthesize Dual donor-acceptor covalent organic frameworks for hydrogen peroxide photosynthesis as in 10.1038/s41467-023-40991-7 and and demonstrate the production of hydrogen peroxide in sunlight?
Was the sodium carbonate decently priced as well?
You say you lost your final product yield from the reagent change but the TLC looks pretty good with product being by far the strongest spot and no starting material, any chance you just lost lots in the workup?
I don't mean this to sound negative, love the videos
I really hate it when people run column chromatography even for a solid product. Why can’t you either solubilise your product selectively or your impurity selectively? These three reactions are straight forward and always yield high. I have done 1000+ organic synthesis and never ran a single column chromatography and yet I got NMR pure products.
Finally some TLCs
I wonder why THC has such a positive effect on the tremors and motor functions of people with PD
THC increases dopamine in your brain
That last shot made me cringe and hide for a sec. Oof😢
Do you think you could make enough for your local community?
This would be very powerful direct action for the people.
The cost of reagents, labware, and time for this synthesis would make your homebrew batch much more expensive than the generic version of this medication, unless you give it away charitably, and the stuff you make might very well kill someone if it isn't properly purified. The point of this video is not to make your own medication, it's exploring the chemistry of how these sorts of drugs are made.
@@Spencergolde
He already has the equipment and no doubt there are others in the community too
I highly doubt that, have you seen the cost of insulin in usa? They're killing people for profit.
I'm not recommending brewing it with rusty spoon and substitutes made by a deranged lead worker. I'm aware of the risks, he spoke of them in the video.
But some with some medicines their absence = death. Given a simple waiver and a genuine desire to help, skilled amateurs such as this benefactors of this channel, could save lives.
I don't know what could be better motivation. And perhaps those he helps could band together and help him in help him cover costs.
Either way it was a question for him. Put speculation is neither here nor there.
@@sarchlalaith8836 I doubt someone would like to take this not well researched, homemade, not properly purified product instead of using a drug prescribed by a doctor, which will not cost much at all because people have proper health insurance in the netherlands
Making experimental drug to treat people? Extremely bad idea. Firstly, by far most drug candidates fail either due safety or efficacy issues. Secondly, many medications need blood tests etc doctor supervising in order to control possible serious side-effects. Thirdly, it would be illegal and you could even be liable if some one dies.
Overall, irreversible non-selective MAO inhibitors have decades of research behind their use, and have increasingly been shown to be less, not more, dangerous than more commonly prescribed medicines in the classes of antidepressants, antiparkinsonians, etc. Anyone genuinely interested should start with reading Dr. Ken Gillman's papers on the topic.
like breaking a key off in a lock
"here, i made you some parkinson's medication, it might have some neurotoxin in it but i'm sure it'll be fine"
no, I wouldn't take it either.
Great work, (and important)
i clicked on this video and i was already liked.
Don't you think this flask is extremely too small?
No, just too full.😀
d3 can dothe same....
then shouldn't psychotropics work with Parkinsons?
Yeah i wonder too. Reading some paper titles i see more talk of dopamine reuptake inhibitors or dopamine agonists than like dopamine releasing agents. But i'm no expert.
Cannabis may help with parkinson's afaict. There's that one viral video about it.
@@user-yw9mw9hv8o the cubes with chocolate would have both MOI and the agonist
Wow!
I want to start a Go Fund Me for a rovac.
ASMR 7:56
Meanwhile lsd and limestone exist
first
Good job Ligma Baldrich
@@Chemiolis it's been an honour
And then 5.93 grams of chipmunk
Lekkere
A L- molecule that is active, even as a prodrug...a bit surprising considering how the majority of active forms are in the D- (dextro) enantiomer form.
Are they actually? I feel like there shouldn't be a huge bias averaged over many different compounds and targets. Anyways, L-DOPA (and in turn dopamine) are synthesized from tyrosine. And nature overwhelmingly uses L-enantionmers of amino acids, including tyrosine.
@@lunkel8108 I'm not expert on this, but remember reading that there seemed to be a big preference in nature; pretty sure it was D > L, which would make L- aminos preference kind of odd; unless I'm missing something based on cell receptors preferring them etc.
@k4681 It depends on what you are talking about. Almost all chiral sugars (glucose, ribose, etc.) in nature are D. Amino acids are almost exclusively L. These amino acids can form proteins with binding pockets for compounds of either chirality, depending on how they are arranged and what the compound is.
"Homochirality" refers to the fact that nature overwhelmingly uses one particular enantiomer of any given substance, not that all of them are exclusively D (or L). You also have to remember that the D/L nomenclature is pretty arbitrary. There are other ways to categorize enantiomers with for example +/- or R/S nomenclature and these don't 1:1 correspond to eachother.
Ooopsy. Bye.
Uupsie 😂
I hope someday we cure these degenerative diseases. There's a likelihood that I'm going to get Alzheimer's when I'm older, so it would be nice to avoid that
I hope someday nobody turns sick.
Cilantro(corriander), spirulina, chlorella, dandelion, fennel seed and many other herbs help with removing toxins especially heavy metals from your body (one of the main causes of dimentia is aluminium for example). eliminate any heavy metals in your diet/body products and eat less processed foods get sunlight and exercise. Stay wise stay healthy, love ya.
I'm a retired synthetic organic chemist. I really enjoy watching your videos. Good to see these reactions and the chemistry.
How would I find synthesis data for emeramide? Looking this stuff up online is hard these days the way they hide websites now
Studying medical chemistry, this hit my spot. Bedankt hiervoor;)
The chipmunk voice on the tongue-twister had me in stitches. Good to see that you're human too. Some people were starting to have doubts.
You might be interested in looking into Dry Column Vacuum Chromatography (DCVC) for those types of large-scale column purifications. Uses less silica and solvent, but does require a specific type of silica.
I have half-ass tried it before, I have the silica from Merck but I gotta try it again sometime to see how well it really works
DCVC is so overrated, there‘s a reason why it never blew up
Hate using Pd(PPh3)4 due to the TPPO impurity’s formed 😂 Pd(dppf)Cl2 is much better and is more stable
what do you mean with TPPO?
triphenylphosphine oxide@@EbbeLoos
@@EbbeLoos triphenylphosphine oxide
thanks:)@@chemistrycapital
Very nice video!
The amount of celite is horrifying! such an amount will make a pretty wide band of mix on silica with decreased separation :/
As it is lab scale, it could be beneficial to use other methods (silica pad only to cut out tar and most Pd, bisulfite adduct for aldehyde purification and just protonating amine, to separate it from non-basic stuff in the mix),
Love TLCs!
The time to use that fancy reductant has come!
when new video?
A more economical way to the Suzuki coupling is the Gomberg-Bachmann reaction reacting a diazonium salt, in this case 4-trifluoromethylaniline with Benzaldehyde in alkaline medium to obtain the final product.
King 👑
What the hell was that catalyst at the beginning of the synthesis???
Pd(PPh3)3 ?
a very common one in palladium coupling reactions
@@josefanon8504still looks wild though
@aidange8863 @josefanon8504 it‘s Pd(PPh3)4. very easy to make
@@user-zo2ie1ml2d
oh thanks, don't know how I made that mistake.
It won’t cure it but it may help some people if it’s better then other maoi b inhibitors
Make testosterone ethanoate
SME aren’t what pays as they are (obviously) too simple to recreate.
Biosimilars have a different approach for market approval, they have to show the. are similar (not the same cell line used for upstream manufacturing )as it isn’t generic.
generics don’t have to prove they have the same kinetics nor efficacy as the original product, just same identity.
biologics are far more complex to manufacture and also to copy hence there is a drive to use as much biotech as possible.
this is the result of India vs. Novartis..
Yoo wth is that?! 3:42
short path distillation apparatus my beloved
Loved the video! I'm very interested in the clamps you used for your column, they look really useful.
It’s better basics smartrack
@@Chemiolis It looks super nice, but it's also relatively expensive. 600-1000 bucks for some folded aluminum and polymers for a single workspace is quite excessive…
Building something comparably sturdy, yet cheaper with some extruded aluminium profiles (I-type / with T-slot) from the hardware store should be a nice side project.
Ah good old Suzuki coupling. So many flasks broke in our lab course while degassing with freeze-pump-thaw.
Also, judging by the mucus colour, your solution was not quite degassed. Git gud >:) Should stay a nice pale yellow after adding in the tetrakis.
May explain the side products though
Is this about ariadne? I've been fascinated by this since seeing it in PIKAL and listening to the Mike Cunningham interview on Hamilton Morris's podcast!
Where did you get your stone heating mantle
This is really interesting to see! Where do you find the information for these videos?
Is it a prodrug?
12:26 Ah shit, I can hear the pain
Why go for Pd(PPh3)4, when Pd XPhos G3 is the same price per mole with much higher performance?
Pd(PPh3)4 has a molecular weight of 1155.56 g/mol, while Pd XPhos G3 has 846.45 g/mol. 1 g of the former costs about 50€ on Sigma Aldrich, or 12,50€ for 250 mg, while the latter costs 80€ on sigma. Xphos pd 3 is way more expensive, the difference of molecular weight is only like 73%. Using xphos pd g3 would be a waste even if you could theoretically use less catalyst because he doesn‘t do proper synthesis under inert conditions
Keep doing what you're doing.
I'll try it
Two questions, would palladium on carbon work as a catalyst? (Ie is there a specific need to use Pd(PPh3)4?) second, did you recover the catalyze afterwards?
I'm not an expert by any means, but as far as I know a ligated palladadium catalyst (Pd II+) is commonly used as the reactive species for this kind of coupling reaction.
Pd/C is generally used for hydrogenations, whereas the Ligands of the Palladium Complex can be specifically tuned for improved reactivity/ selectivity on
coupling reactions regarding substrates/educts (and stereochemistry).
Pd/C can be used as a coupling catalyst (like a Suzuki coupling in the video, or for Stille coupling) it might be less efficent, or you would need a co-catalyst
Hope this helps, further information might be in the literature links at en.wikipedia.org/wiki/Palladium_on_carbon
@@moritzwebers7986thanks, it makes sense ig it would be much less efficient since pd/c is better fo rhydrogenations
There are some Suzuki couplings that have been done with palladium on carbon
does this mean i should lay off my regular use of 500mg+ diphenhydramine (i dont have pd)?
No.
The regular use of diphenhydramine has been linked to dementia. So yeah, you might want to quit if you don’t want dementia. On the other hand, I’m not your mother so you don’t have to listen to me.
When you google for alzheimer's, but all links are purple.
This needs mostly for youth not for boomers
This is probably the most legally-dangerous-for-yourself video you've uploaded. Keep it up. Make those rich suits cry.
Not really. The reagents, labware, and time costs are going to be way higher than this medication would cost as a generic. And the generic drug would have been made in an FDA (or other country's regulator) compliant lab. Also most of the chemicals used are sourced exclusively from chemical vendors that won't sell to individuals
@@Spencergolde All of that's immaterial because this features filming a patent violation. Also, supply houses will sell these reagents to ME, so I figure they'll sell'em to anybody. I have no special qualifications.
@CloudCuckooKing I don't know if it's different in south korea where this patent is filed, but in the U.S., there's nothing illegal about filming yourself following an open-source patent. He also changed part of the procedureto use a different reducing agent, so depending on how the patent is worded this might not be a protected process. Patents aren't meant to keep you from doing something, they're meant to prevent people from selling something. And, really? So when you're checking out at Sima or any other chemical supplier, what do you put in the required field asking for the name of your business or institution? Or the directory of your receiving department? Because I have ordered chemicals during my research work at university and can say there's no easy way around this. If you file an LLC as an online educator, you can apply that when ordering chemicals, but you still need a non-residential address to ship to. Again, not impossible, but it's a hurdle in addition to cost, complexity, and the lack of lab standardization that would make any product from this very expensive and not safe to use.
@@Spencergolde In the US, using a patent even for personal use is a violation. You're absolutely right about the catalyst change probably changing the situation though. They ARE actually meant to prevent any unlicensed use of the technology contained in them, not just sale.
I mean, the one that comes to mind is Sigma, though they're probably not optimal due to expense, and while I am generally loathe to register for anything, registration at checkout does not request any such field.
Expense and safety of use of the product is entirely irrelevant still. Doesn't need to be commercially viable, doesn't need to be used at all, just needs to follow the procedure (which you are right, he may not have accurately done).
@CloudCuckooKing Wow, I did a deep dive into ACS standards of chemical patents and learned something new. You're right, under certain circumstances the very act of carrying out a synthesis procedure can be classified as infringement. Which doesn't really make sense, especially since the procedure is published common knowledge. Weird.
But I still find it hard to believe you can buy from sigma without an institution. Sure you can buy some things off ebay or Amazon, but the specialized reagents in this video are going to have to come from a big vendor
"Fluorine exists at standard conditions as a highly toxic, pale yellow diatomic gas. Fluorine is extremely reactive, as it reacts with all other elements except for the light inert gases"
Am I the only one getting ticks from seeing the molecule depiction and relating to the quote from Wikipedia?
- I mean, certainly this molecule will not break down in the brain.. Right....
Chemistry is wild, might break down before the brain if the correct form isn’t produced properly
@assidy5026 So it will 'just' be highly toxic elsewhere?
I guess it's choose your poison - shake or shrivel 🥵🥶
You are referring to the fluorine atoms in the trifluoromethyl group right? Those are used because the C-F bond is incredibly strong. Replacing hydrogen atoms with fluorine limits the metabolism of the drug at that location. Without them you generally get toxic metabolites.
@070 Yes, the 3 fluorine atoms at the end of the molecule (to me, those that seem like they're out looking for trouble, and since fluorine does not have a good reputation from where I'm from I ...)
I just looked up fluorine on Wikipedia and was a bit surprised when I saw its Oxidation states: −1, 0 (oxidizes oxygen)
I don't know why, but I imagined it to be more like carbon with its -4 to 4.
I presume the trifluoromethyl group is extremely stable and not metabolized by the body and fully excreted - making it a 'safe' drug?
Thanks, I learned something useful and exciting today :ø)
@@EgonSorensenIm sorry bit you dont seem to have much background knowledge on chemistry, you should learn a bit more before making such bold statements