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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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sekio

sekio

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This is the place to discuss the various chemical and biological implications of novel and well-known drugs that don't deserve their own thread.

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i've read pihkal about 4 times over, and sometimes when i do my crazy ass brainstorming i imagine that i am bouncing ideas off of sasha. tonight i was thinking about how some ligands can bind permanently to receptors. (here, i am assuming that full agonists tend to bind permanently more often than partial agonists, idk for sure if that is true or not).

i had an idea, that it might be possible to get "permanently" bound ligands off the receptor by introducing a second drug that is a competitive partial agonist at that receptor but with a much greater binding affinity than the primary drug in this example. might be rare to find such a molecule, and idk if it is even possible for a drug to have both of those properties, but i feel it is worth pondering over nonetheless.

at first i looked at the problem like sasha would. i wouldn't want to waste time in the laboratory with rats and petri dishes, i would jump straight to self-administered in vivo testing to test such a thing if i thought "permanent" binding had happened to me. in this case, the most immediate means of telling if your experiment had the desired result would be by monitoring your own consciousness as the drug progresses in its action, of course. however, that is far from conclusive. you might be able to monitor your urine and excrement as a means to determine if the experiment was a success or not, but that would be messy. (and no matter what, hopefully you will never actually find yourself in this situation!)

i then had a thought, and asked sasha, "wait, in this case would it actually be much quicker and easier to radiolabel some ligands and test the theory in vitro?"

then i had the thought "god dammit i shouldn't be able to ask a question like that, i haven't even taken organic chemistry yet, i wish i was in school right now." lol :) they told me at the last minute this fall that i needed to pay for my own classes this semester, since i dropped out of my last semester there. soooo i won't be starting up again until the winter, not that i was very far yet.

[/insomnia]

[insomniaedit]perhaps would be most effective with multiple administrations, and you may need other methods to induce metabolism or excretion while the bounced pseudo-permanent agonist was in extracellular space. maybe plasmaphersis would be the best choice at this stage (sort of like treating bromism)? once its kicked off the receptor though there would only be a small window of opportunity to get it out of the subject somehow before the second drug is metabolised.

this might be some phizer level pharmacology/biochemistry here i realize :) discovering just the right antidote drug would take quite a bit of work i am sure. as a matter of principal, though, i refuse to believe that anything can be absolutely permanently bound to a receptor. heh :) [/inso..
 
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I think if something covalently bonds to a receptor, that receptor is destroyed. It's the same principle as irreversible MAOIs.
 
If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.
 
very interesting.

it would be possible for a receptor to have a covalently bound ligand that is bound in such a position/conformation that another ligand could still bind to the receptor, no? since two molecules can bind to two completely different sites on the same receptor.

also, what if you could use a covalently binding agonist to your advantage in some way? for one example, perhaps the covalently bound ligand could allow an entirely new type of ligand to bind to the receptor, a ligand that could not have bound to the receptor before. creating new avenues for signal transduction in that way.

take nature's receptor design and improve upon it somehow :)
 
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For the former, that would be called an irreversible allosteric modulator.
 
Does anyone know the affinities on 5-HT, DAT, and NET for
Dextro, Levo, and Racemic Methamphetamine/Amphetamine
 
Could there be (given methodologies for in vitro binding and release assays)? Would the mean between the d and l isomers provide a rough indication?

ebola
 
ebola? said:
Could there be (given methodologies for in vitro binding and release assays)? Would the mean between the d and l isomers provide a rough indication?

ebola
Click to expand...

i was thinking that as well. i don't think a simple mean will do it though, it looks like the numbers change exponentially as potency drops. but yeah i am pretty sure that there has to be some kind of a direct correlation between R and the individual values for D and L.
 
Ah, here is a good place to pose this question. I wanted ADD answers to most likely a BDD question. I'm currently wrapping up day 3 of opiate withdrawal. Nothing too terrible but probably on par with the worst I have experienced before. As far as I've always been aware, your classic opiate painkillers (oxycodone and hydromorphone in particular for my use) are not toxic in the slightest, and that the health dangers occur with complications related to IV use, overdose and addiction. Well I have IVed a little, never overdosed and have on and off had some light dependencies but nothing major. But the withdrawals I get don't feel 'benign'. Very achey, bones are crackily, neck is stiff, headache, etc. Now, is this 'bad' for me? What is going on in my body that is causing these symptoms? Is it simply downregulation of mu-opioid receptors coupled with a lack of endorphins that is balancing, or are there some toxic processes to it as well? It feels awfully gross and toxic, but withdrawal can be tricky and the mind is a powerful thing.

In addition same question but now posed to benzodiazepine/GABAergic withdrawal, assuming it is not to the point of having a seizure, again just mild-moderate withdrawal. Feels god-awful, but is it all in the mind or are there toxic processes occurring?

Thanks!
 
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comt

i asked on a different thread about comt inhibitors
this is my original post:
Hi
Is anyone knows what comt enzymes tend to degrade more: dopamine, norepinephrine, epinephrine? And in what ratio?
Thanks
Click to expand...

Epsilon Alpha said:
http://pharmrev.aspetjournals.org/content/51/4/593.full.pdf
Page 596 will have your answers, please post questions like this in the Big and Bangin' thread.

But its sort of a 1/1.5 DA/NE affinity ratio.
Click to expand...

now, thanks Epsilon, if i'm not wrong the arcticle said that COMT tends to dergade NE 1.5 times then DA, but also tend to degrade much more L-DOPA that eventually if i will take COMT inhibitors it will increase more of my dopamine then noradrenaline? or i'm wrong? sorry, my english just not so good, i just would like to know if i will take comt inhibitors like "entacapone" what it will increase more eventually NE or DA and in what ratio
 
opiates cover up your every day aches and pains. these aches/pains are bound to feel WORSE than baseline after a period of opiate use/abuse. just the natural course of things.
 
sekio said:
That's why they're withdrawals.

You'll make it.
Click to expand...

Touche good sir. Indeed I'm feeling much better today, been through this many times, but I've always just wondered what is going on in there. Of course withdrawal tends to take the form of the opposite effect to what the effect of the drug is, so pain killer will lead to pain...But my real question, to make this ADD material, is what is going on to cause these symptoms? Any toxic processes occurring or merely the balancing out of mu receptor down-regulation plus decreased production of endorphins (and naturally, lack of opiates)? I did feel a lot better this morning though (4 full days from last dose) and even went for a 20 minute run and light work out after which was painful, but made me feel a lot better.

thenightwatch said:
opiates cover up your every day aches and pains. these aches/pains are bound to feel WORSE than baseline after a period of opiate use/abuse. just the natural course of things.
Click to expand...

Ah, so this is sort of a glimpse into what I'm in for in the future, perhaps 30-40+ years down the line? (I'm 21) I did describe myself as feeling like an 80 year old man to my buddy, haha. This makes sense, but I'm surprised I have pain in so many areas...!
 
vortex30 said:
Ah, here is a good place to pose this question. I wanted ADD answers to most likely a BDD question. I'm currently wrapping up day 3 of opiate withdrawal. Nothing too terrible but probably on par with the worst I have experienced before. As far as I've always been aware, your classic opiate painkillers (oxycodone and hydromorphone in particular for my use) are not toxic in the slightest, and that the health dangers occur with complications related to IV use, overdose and addiction. Well I have IVed a little, never overdosed and have on and off had some light dependencies but nothing major. But the withdrawals I get don't feel 'benign'. Very achey, bones are crackily, neck is stiff, headache, etc. Now, is this 'bad' for me? What is going on in my body that is causing these symptoms? Is it simply downregulation of mu-opioid receptors coupled with a lack of endorphins that is balancing, or are there some toxic processes to it as well? It feels awfully gross and toxic, but withdrawal can be tricky and the mind is a powerful thing.

In addition same question but now posed to benzodiazepine/GABAergic withdrawal, assuming it is not to the point of having a seizure, again just mild-moderate withdrawal. Feels god-awful, but is it all in the mind or are there toxic processes occurring?

Thanks!
Click to expand...

Have you studied much into the Kappa Opiod Receptor? It is the receptor that deals directly with opiate dependence and some of the withdrawal symptoms associated with that. It has been some time sense the last time I studied it but I believe there are several scientific journals that state that as you continue your use of opiate agonist, the K Opiate receptor grows. And as the K receptor grows, so does the tolerance to opiates and with that increase also comes how bad the withdrawal symptoms are.

Little bit of interesting knowledge about the K receptor, there are 2 well known drugs that activate this receptor - Ibogaine and Salvia Divinorum. Of those two, Ibogaine actually has been scientifically proven to cause shrinkage to the receptor, but at the expense of a earth shattering visual experience. BUT it is used very successfully to alleviate the addictive symptoms and withdrawals of Opiates, in particular heroin. It also is has been shown to drop opiate tolerance as well. There are clinics world wide called Ibogaine clinics and they specialize in the treatment of addiction.

The problem with ibogaine though is that it is not always an easy one to get your hands on, plus a 24 hour spiritual journey is prob not exactly what you are looking for. Now salvia on the other hand only last upwards of 30 min or so (3-4 hours if you hold the plant in your mouth for 30 min- but it taste like you are eating grass).

I spent the better part of more then 10 hours trying to discover if salvia may have some of the same anti addictive properties as ibogaine in that they both hit the same receptor in similar ways. I did find an article about it being used in one case study of a woman with a hard to treat case of depression using it to fully relive symptoms. But there has never really been a study on salvia's ability to relive opiate withdrawal symptoms. My good friend and I joke all the time that maybe its time to bust into some salvia to drop our opiate tolerance.

Thats my 2 cents. Sorry I did not post any links to scientific articles or journals, I did not want to spend 2 or 3 hours tracking down all the papers I have read. Most of it can be found in pub med through articles linked on wiki about these subjects.
 
I think that you need citations. A good bit of this sounds unsubstantiated. In particularly, receptors don't "grow" or shrink. Rather, populations of receptors may be upregulated or downregulated (among other fates, under varying biochemical conditions).

ebola
 
I once used a mixed mu-kappa agonist (caused horrific hallucinations only slightly above the recreational mu effect dose-range which lasted for a good 45mins to 1.5 hours) for a decent while and was badly dependent on it. I will inform you that it did not make the material in question any less addictive or physical-dependency forming. It did not prevent the development of tolerance, either - well, for the mu effects anyway - the kappa effects seemed to always require the same amount of material. You can probably see what happens here.

Good riddance.
 
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