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LAT1 ligands to bypass the BBB

kyanite

kyanite

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Oct 15, 2005
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Large Neutral Amino Acid Transporter Enables Brain Drug Delivery via Prodrugs

Mikko Gynther, Krista Laine, Jarmo Ropponen, Jukka Leppänen, Anne Mannila, Tapio Nevalainen, Jouko Savolainen, Tomi Järvinen, and Jarkko Rautio

Department of Pharmaceutical Chemistry, University of Kuopio

Abstract:

The blood−brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug−substrate conjugate is able to transport drugs into the brain via LAT1.

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As a model drug, they used Ketoprofen, which is a pretty useless example because the 9-carbon backbone(lengthwise) is pretty damn rigid and the whole ketoprofen molecule is pretty damn planar. Does anyone have knowledge of how much space is in the LAT1 binding site? Or how similar to the human transporter is the rat transporter?
 
so from what i understand is that one would be able to get loperamide to cross the BBB via LAT1 transporter? Or increase the probability and likelihood for compounds transported by LAT1 to cross the BBB? That sounds pretty darn interesting.
 
the problem with loperamide is theres not really anywhere to attach it to the tyrosine. If you're well prepared and willing to throw on a carboxyl or hydroxy group somewhere you might as well make something else...

the hydroxy group already on there brings back memories of MPTP(danger), and the amide group looks necessary for opiate action. i personally hate loperamide ever since someone claimed to have smoked gas-soaked filtrate, like seriously, what the fuck. this drug has a cult following.

by the way, any other drugs that might be interesting?
 
kyanite said:
i personally hate loperamide ever since someone claimed to have smoked gas-soaked filtrate, like seriously, what the fuck. this drug has a cult following.
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what the mighty fuck 8) ? That sounds a lot like Jenkem. You might want to combine those together. Seriously. What the fuck? Gas soaked filtrate? Did he burn himself? Lol. Any links by any chance, since i want a good laugh :D q
 
about the LAT1:
abstract: http://molpharm.aspetjournals.org/cgi/content/abstract/61/4/729

Basically it looks like for transporter action, the prodrug requires the isolated amino acid portion of the tyrosine to bind, and a hydrophobic, not bulky attachment. The prodrug should be hydrophobic enough to bind to the transporter well, but not too well that it cant escape the protein after shuttling across the BBB. A molecule will block the transporter if it's affinity is too high, or if it's too bulky, for examples melphalan, triiodothyronine, and thyroxine.

Although this article gives examples of the general rules for ligands, it doesn't really address SAR or mapping of the cavity too in-depth...


And also the LAT1 transporter is expressed all over the brain, from the grey to the white matter region as found in J. Cereb. Blood Flow Metab. 2000, vol 11, article starts on page 1557
 
Man, you can always count on loperamide showing up on any discussion about the BBB. I personally don't see what is so attractive about it, what would happen if someone actually tried something that worked and ending up with a ton of ultrapotent opioid in their brain?

Back on subject, would a L-tyrosine conjugate actually increase the passage of a compound that is already permeable to the BBB? Or could this actually hinder the rate of crossing? I guess what I am asking is this only useful for molecules that already can't get across?
 
If you want to get loperamide into the brain, you use a P-gp inhibitor. It's not an ultra-potent opioid, but it's not one I want in my brain at all.

though now that I realize Sertraline is a P-gp inhibitor, I'll probably have to put some in there and see how it goes.
 
^ From what I heard from people who did the p-gp inhibitor trick, Loperamide is actually a very dirty and edgy high, and one that they'd rather not experience again.
 
Yeah, that's what I'd expect. I wonder how much I'd have to take to break through my suboxone.

Everyone goes on and on about how to get it through (acetylation, insulin+cyanocrylate "nano-particles") when it's so freaking simple.
 
apparently the trouble with some nanoparticles is the elimination and build up of them in places(read: brain) you dont really want to have used, empty nanospheres in...
 
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in europe, there's a medication against headaches which contains ibuprofen-lysinate. i'm wondering if this complex would be stable once having entered the bloodstream (we know, hydrochloride and other salts don't).
and would lysin be overly a ligand for the carrier or would it be to basic/postively charged?
i'm considering this as i think that ibuprofen in the brain would possibly bear some quite healthy effects; psychosis and other psychological conditions being thought as a chronic inflammation of the cns and such theories...


ps: please leave the loperamide in your intestines and forget about acetylation and other ridiculous stuff, what would we all do if we couldn't further use loperamide against our diarrheas :o
 
Schnitzalted said:
I personally don't see what is so attractive about it, what would happen if someone actually tried something that worked and ending up with a ton of ultrapotent opioid in their brain?
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well, if it had mu-selectivity and behaves as we think it does?
What would a super-potent-opioid do in your brain? Well, think about that for a second ;)
 
Big time caution

Don't chemically mess with loperamide. It is too easily dehydrated into an MPTP analog, and i'm sure everybody here is aware of what that means. And to acylate the 4-piperidyl hydroxy group and/or try to turn the cyano group into something that would make the molecule more BBB penetarble is just asking for a very bad molecule, One that you don't come back to earth after your trip! I'm DEADLY serious here. Just leave loperamide alone (synthetically speaking)
 
Bondmaker said:
Don't chemically mess with loperamide. It is too easily dehydrated into an MPTP analog, and i'm sure everybody here is aware of what that means. And to acylate the 4-piperidyl hydroxy group and/or try to turn the cyano group into something that would make the molecule more BBB penetarble is just asking for a very bad molecule, One that you don't come back to earth after your trip! I'm DEADLY serious here. Just leave loperamide alone (synthetically speaking)
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totally agreed. A few months ago I posted a whole load of links which showed that if loperamide got into the brain it was a very effective neurotoxin a la MPTP. Not hypothetical, it killed baby pigs (who have incomplete BBB's) very effectively and wrecked monkeys too. very few people listened. so fuck em. let selection take its course.
 
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Duuhhh,,

I meant dimethylamido in loperamide. i was thinking of the the cyano group of a similar molecule , diphenoxylate, which was the compound of choice as an antidiarreal before loperamide came along. Diphenoxylate grew out of the demerol class of molecules where the ester at the 4-piperidyl position is 4-carbon first, rather than 4-oxygen first. Sorry about that chief, us old farts have a lot of molecules in our gourds and tend to get cornfused, yanowahtimean?=D
 
morphiquet said:
so, my question stays wether ibuprofen lysinate dissociates in aquatic medium and which implications ibuprofen in the brain could have on mental health.
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I dont know jack shit about how NSAIDs work, and i dont think theres a definate answer as to how they work exactly, but if i remember right, it doesnt target the brain to produce pain relief.

as for the lysine salt, the way the ibuprofen and lysine are attached together is through acid-base interactions where the hydrogen of the carboxylic acid in ibuprofen is lost to one of the amines of lysine. in solution, the ibuprofen lysinate is "torn apart", and found as ibuprofen-(CO2-) and lysine-(NH3+) ions that float around independantly.

Now, I'm just an undergrad, but from my understanding, in solution(ie bloodstream) this lysinate salt doesnt exist, but is in independant ions, of which the lysine will be transported, but the ibuprofen wont be. Now, in reality, ibuprofen is a weak acid, and so there'll probably be more ibuprofen + lysine than (ibuprofen)- and (lysine)+ in solution, but i dont have the k value of that equilibrium at hand to know the extent of ion formation.

the point is tho that in solution, it isn't one conjugated molecule. the ibuprofen and lysine isnt covalently(e.g. carbon-carbon) bonded together, but ionicaly bonded(e.g. Na+ and Cl- in water) and wont be conjugated in the blood stream when it reaches the LAT1.
 
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