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Bupe "Less is More" ... not so fast

and if it did let's say, is there knowledge out there that norbup would override the bup and not be blocked? ? I'm not saying there isn't facts that prove norbup would override everything on the receptor, I'm just asking everyone..
I just saw that the slow dissociation konstant of bupe is responsible for the blockage https://www.reddit.com/r/DrugNerds/comments/4v4dgu/crazy_buprenorphinenorbuprenorphine_facts_that/
slow off-rate/long residence time. Binding is pseudo-irreversible.
So imo norbupe shouldn't be able to override the bupe, but https://www.ncbi.nlm.nih.gov/pubmed/22469638
For the doses administered in this study, buprenorphine and fentanyl showed an additive interaction.
so maybe bupe and norbupe can have an additive interaction too
 
i think less is more cuz some receptors are still open to let you feel the next dose, if you dose high every day your brain is just always full of bupe so you dont notice it.

The question is, how often is the receptor activated when bupe is bound. The intrinsic activity is around 0.4 iirc so bupe doesn't activate the receptor as much as say morphine. Due to the high dissociation constant it takes a while till bupe unbinds and goes back to the synaptic cleft. If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again. But if you take a low dose you can stagger the effect by taking low doses a few times a day.
 
I'll duplicate the thread and move one to Neuroscience and Pharmacology Discussion
 
I just saw that the slow dissociation konstant of bupe is responsible for the blockage https://www.reddit.com/r/DrugNerds/comments/4v4dgu/crazy_buprenorphinenorbuprenorphine_facts_that/
So imo norbupe shouldn't be able to override the bupe, but https://www.ncbi.nlm.nih.gov/pubmed/22469638 so maybe bupe and norbupe can have an additive interaction too


Ahh ha just clicked on that link to read and I see he pretty much as the same concern as me especially with PGP, but he seems to be much more knowledgeable of the subject =D

and thank you for the links, this one especially even though he a grad student, it seems to have good logic with theory..

And funny you put that about bupe and fent because this is what I was currently writing::
** Also does anyone know the strength of Norbup alone as a full agonist. I did read somewhere that's it's stronger then bup itself, I'm guessing it's a naturally occurring synthesized product of bupe wen metabolized lol, well not really, but similar .. but I'm guessing it would be almost as strong as fentanoyl, because bupe as a partial atagonist is already stronger then heroin in that sense.

So with that being said maybe norbup is very very strong and in that case maybe it can have an additive interaction with bupe.

im also goin click on article before I start fishing and read, because I was about to say okay it can't override bup it may seem (which I didn't knit would, but who knows) but I was goin again say how can bupe/Nor even have an interaction . But I will shut up for a minute and read , because that may help me understand how bupe works even better, again thanks. Thanks to all of y'all so far.
 
I'll duplicate the thread and move one to Neuroscience and Pharmacology Discussion

Thats a good idea,thank u again, many people over there may have a good understanding, are u allowed to also leave it here as well? I think many people in this area could have great answers as well.
 
Are u allowed to also leave it here as well? I think many people in this area could have great answers as well.

I moderate this sub-forum, so yes, I can leave it here as well :D
And normally you don't get many views/replies in N&PD so duplicating seemd to be the best idea to get as many replies as possible
 
The question is, how often is the receptor activated when bupe is bound. The intrinsic activity is around 0.4 iirc so bupe doesn't activate the receptor as much as say morphine. Due to the high dissociation constant it takes a while till bupe unbinds and goes back to the synaptic cleft. If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again. But if you take a low dose you can stagger the effect by taking low doses a few times a day.

To piggy back of what u said to burn out: (w/questions)

1. I know that bupe doesn't activate the receptors like morphine, etc.. but what is that number 0.4 iirc indicate? , And what's "iirc" maybe the terminology is obvious and right in my face lol, but I never learned that before, interested to know.

2. u stated as a example : "If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again"
-so are u saying after taking a dose where all receptors are activated it would take 5 hours to unbind and be activated again, or 5 hours to unbind and another 5 to be activated? Ima little lost here?

** I would of guessed they would have similar affinities, maybe almost identical in that sense, I also wonder how closely similar they are in molecule form..I've seen a pic of each but never really examined both
 
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I moderate this sub-forum, so yes, I can leave it here as well :D
And normally you don't get many views/replies in N&PD so duplicating seemd to be the best idea to get as many replies as possible

Awesome im about to check that section of the forum, no clue we had that. To be honest I've never been in any section of this forum besides this section /other drugs/ -and psychedelics
 
To piggy back of what u said to burn out: (w/questions)

1. I know that bupe doesn't activate the receptors like morphine, etc.. but what is that number 0.4 iirc indicate? , And what's "iirc" maybe the terminology is obvious and right in my face lol, but I never learned that before, interested to know.

2. u stated as a example : "If bupe activates the receptor just once (most likely imo) and takes say 5 hours to unbind taking a high dose will activate say all 100 receptors once but it takes say 5 hours till the receptors can be activated again"
-so are u saying after taking a dose where all receptors are activated it would take 5 hours to unbind and be activated again, or 5 hours to unbind and another 5 to be activated? Ima little lost here?

** I would of guessed they would have similar affinities, maybe almost identical in that sense, I also wonder how closely similar they are in molecule form..I've seen a pic of each but never really examined both

1. 0.4 indicates the intrinsic activity (
Intrinsic activity (IA) or efficacy refers to the relative ability of a drug-receptor complex to produce a maximum functional response. ... Agonists of lower efficacy are not as efficient at producing a response from the drug-bound receptor, by stabilizing the active form of the drug-bound receptor. Therefore, they may not be able to produce the same maximal response, even when they occupy the entire receptor population, as the efficiency of transformation of the inactive form of the drug-receptor complex to the active drug-receptor complex may not be high enough to evoke a maximal response. Since the observed response may be less than maximal in systems with no spare receptor reserve, some low efficacy agonists are referred to as partial agonists.
) I too don't understand exactly what that means, imo either that the hyperpolarisation/depolarisation or activation of second messangers is lower thatn with a full agonist or a partial agonist doesn't activate the receptor each time it binds to it
IIRC = if I remember correctly
2. This: after taking a dose where all receptors are activated it would take 5 hours to unbind and be activated again (but thinking about it again I don't think that's the right explanation)

I think norbupe is bupe minus cyclopropylmethyl http://read.nxtbook.com/agilent/agilentbooks/drugscreeningecompendium/application1/Figure1.jpg
 
https://www.ncbi.nlm.nih.gov/pubmed/2055424
1. Doses of buprenorphine (0.01, 0.1, 0.5, 1, 5, 10 and 50 mg/kg) were administered to determine buprenorphine's ability to precipitate abstinence symptoms in morphine-dependent mice. 2. When buprenorphine was administered in the fourth day of morphine addiction, the results demonstrate that the administration of the partial agonist opioid produce a bell-shaped dose-response curve. 3. The highest dose (50 mg/kg) was partially inactive while lower doses causing similar percentage than group treated with naloxone with respect to the appearance of the most of the symptoms of abstinence studied (diarrhoea, tremor, shaking-"wet dog shakes"-, jumping and weight loss). 4. Our findings demonstrate the bell-shaped response curve of the antagonist effects of buprenorphine.
 
So basically the The .4 indicates how much of the receptor is being activated naturally. Do u know the maximum number for instance 1.0, 2.50 , etc.. or there is no limit and it just indicates strictly the activity it produces within the receptor(s)

Also a partial agonist doesn't activate the receptor each time it binds? I know ur only stating a possibility, but I would think it would each time, no? even if it barley does at all, I would think it would in some form or the other? I can't wrap my head around That part, even though it would answer a lot if that were the case..unless there is something I'm missing or not understanding.

and that's interesting to learn Exactly to the tee on why there "partial" agonist, I mean the name itself is self explanatory, but to know that one substance would be labeled as a partial agonist due to its intrinsic activity is quite new to me.

Still as I click on thes links and realize more in depth about bup , the more I feel like I come to realize that less is not more LOL. Only because it seems like bupe takes a world of its own, unlike any other opiod, and I feel like the metabolized norbup from bup would not naturally get in the way of its goal, Unless still it does work as a full agonist while crossing the BBB at a strong enough rate, but facts still show it's still highly affinitive to PGP

But I have yet to look up if bupe is as well, since there so common, and if that's the case maybe it does work the same as bupe wen entering the system. But so far from what I have read and seen it shows that norbupe does not work the same at all really. They just have some similarities , especially if it's only minus C.p.m. (Cyclopropylmethyl)
 
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So basically the The .4 indicates how much of the receptor is being activated naturally. Do u know the maximum number for instance 1.0, 2.50 , etc.. or there is no limit and it just indicates strictly the activity it produces within the receptor(s)

Also a partial agonist doesn't activate the receptor each time it binds? I know ur only stating a possibility, but I would think it would each time, no? even if it barley does at all, I would think it would in some form or the other? I can't wrap my head around That part, even though it would answer a lot if that were the case..unless there is something I'm missing or not understanding.

Intrisic activity is between 0-1 (1 or 100% = Efficacy equal to the endogenous agonist) but there seem to be super agonists with Intrisic activity over 1
I think the partial agonists doesn't activate the receptor each time is wrong, maybe more like the ion channels (for ionotropic receptors) don't open as much as with a full agonist, but I asked in N&PD so we'll see
 
Okay I'll be checking up on that section as well

i read some where not long ago about Super agonist, maybe it was that deadly W-18 crap, I forget.

and yeah that would seem more on par, with maybe the ion channels don't open as much with partial agonist...not saying that's what I think, but that could be a possibility, but I don't think that would answer norbup's possibility of playing a part with being active in lower doses, but I could be wrong or missing something.

and to be honest I had no clue what ionotropic receptors were, had to look it up, and then I felt like an idiot after I did lol. Basic knowledge seems difficult with terminology/words I have yet to recognize lmao
 
I always do 1-2mg doses each time I take my bupe, but I slam it too.. so it wears off much faster than sniffing, sublingual, or any other ROA would, for the most part.. lasts a good 3-6 hours, then I start to feel the WD slowly creep in and I do another 2mg quarter of my bupe(subutex). I believe that less IS more with bupe, no doubt.. sorry i am just kind of scanning this thread, read the first post the OP originally posted, and scanned the rest, i am kind of in a hurry.. just stating my opinion on it.. At doses less than 2mg or just 2mg, i find bupe to be MUCH more therapeutic than at doses 3mg plus... A lot of my buddies, claim that more is more, with bupe to them, just like any other opioid would be.. but i will always argue with them, just to try doing less, and see what happens.. Some did believe me, and read up on the whole less is more theory, and now take way less.. some are very close minded and didn't give it a try at all, claiming 4mg at a time, works way better! and they take like 16-24mg a day... which is wayyyy too much.. Sorry if i am not on the same page, or something with this post.. but being on bupe as long as i have, i just wanted to chime in, with my opinion and experience.. The ROA you take bupe has a lot to do with it too!
 
Well so far me and a few others at the Neuroscience and pharmacology section are now past the point of no return (As of now only lol) regarding if norbuprenorphine effects more euphoria in smaller doses of bupe/sub, and it seems to be false

and according to links and other tests results I've seen through articles, it also seems that norbuprenorphine is weaker , even though it's metabolized from bupe and is a full agonist

I also assume if it was even possible to have norbupe break the BBB and act as a full agonist it would : 1.) it would only be useful in much higher doses and 2.) bupe would override the norbupe anyway....

so it Seems though ;) .. nothing here is fact, but almost fact lol, due to more scientific research flowing to the results of norbup being almost useless when subs or subutex (buprenorphine) are taken in any ROA

That being said it also seems , IMO but also that there's more fact based research to show even bupe alone in lower doses does not seem to serve a purpose in being "more" or more euphoric...

BUT it does seem that bupe at low doses is "beneficial" in a way, which is much different then the "less is more" theory, it's beneficial for the fact u can save money, an addiction, brutal WDs , etc all because the fact if u are not dosing a high amount of subs already (or to begin with) , it seems that 2mg will work the same as 8mg ...
 
To clarify, dissociation constants are not a measure of how long it takes for a molecule to dissociate from it's ligand. It's better to think of it as binding affinity. Unless there's an irreversible binding event, there is a rapid equilbirium, so you could actually think of the molecules as constantly binding and dissociating from the ligand. that's why buprenorphine causes PWD. It's not ripping the full agonist off the receptor or latching onto the receptor for a longer period of time. It's outcompeting the full agonist by having a higher affinity for the receptor.
 
I always do 1-2mg doses each time I take my bupe, but I slam it too.. so it wears off much faster than sniffing, sublingual, or any other ROA would, for the most part.. lasts a good 3-6 hours, then I start to feel the WD slowly creep in and I do another 2mg quarter of my bupe(subutex). I believe that less IS more with bupe, no doubt.. sorry i am just kind of scanning this thread, read the first post the OP originally posted, and scanned the rest, i am kind of in a hurry.. just stating my opinion on it.. At doses less than 2mg or just 2mg, i find bupe to be MUCH more therapeutic than at doses 3mg plus... A lot of my buddies, claim that more is more, with bupe to them, just like any other opioid would be.. but i will always argue with them, just to try doing less, and see what happens.. Some did believe me, and read up on the whole less is more theory, and now take way less.. some are very close minded and didn't give it a try at all, claiming 4mg at a time, works way better! and they take like 16-24mg a day... which is wayyyy too much.. Sorry if i am not on the same page, or something with this post.. but being on bupe as long as i have, i just wanted to chime in, with my opinion and experience.. The ROA you take bupe has a lot to do with it too!

thank your for ur input , and I do wonder that sometimes and think the same thing, even from experience..!

BUT what I came to realize is that I think less is not technically MORE or even more therapeutic for that matter, it's just that if you look at my last post I just stated a couple mins ago , since we seemed to be posting at the same time but anyways...

what I stated was that it's more of bupe being really strong at lower doses, just as strong as the higher doses, especially since it blocks opiates and is a partial agonist, actually being a partial agonist makes this whole thing make even more sense
but it's something that the pharm company's won't tell you, they want u to be taking 8-32 mg a day...and WE all know that, nothing new here

i think the correct theory should be "Less is more beneficial"...

like i I mentioned we went over a lot of articles , espcecially those with test results of this certain topic, and technically nothing so far indicates that small doses of bupe is more powerful, euphoric, or theuraputic but it does seem that less bupe can do just as good as a job as a higher dose

But again!!!! I am no doctor whatsoever, closest I got is a college degree in business lol, Nothing I'm saying is a complete fact, besides the fact that there are fact based articles in the other thread in Neuroscience section and in this one actually , leaning in another direction, but none of them are test results for this exact topic, it can still be debated for that reason
 
To clarify, dissociation constants are not a measure of how long it takes for a molecule to dissociate from it's ligand. It's better to think of it as binding affinity. Unless there's an irreversible binding event, there is a rapid equilbirium, so you could actually think of the molecules as constantly binding and dissociating from the ligand. that's why buprenorphine causes PWD. It's not ripping the full agonist off the receptor or latching onto the receptor for a longer period of time. It's outcompeting the full agonist by having a higher affinity for the receptor.

Yes someone explained that to him in the other section; he told him that once something binds to a receptor it is active as long as it is there on the receptor, rather then work in cycles, I don't know if your getting at the same thing though? Maybe just in diff words?

Actually nvm ur talking about on just how it works lol

BUT ur also stating that regular full agonist become bound to receptor(s) and work by constantly binding and dissociating? ?- and something like bupe actually will bind as well, but outcompete it's host pretty much? Lol So I'm assuming since it doesn't knock it off (because I never understood how it would just knock it off anyway, strong or not) would it bind and barley disssociate unlike its competitor? And is that how it outcompetes and eventually takes over? Or am I completely off track on this one?? Ahhaha

I do ask with confusion, but confidence lol because if it doesn't knock it off and if it doesn't outcompete obviously by just hanging on longer (since PWD happens quick) , I'm assuming the only possibility is that the bupe literally joins on (latches/binds) and either slowly cycles, or just latches on and stays dormant, while the other agonist cycles in and out until there's no more room for it....

-also I'd love to know why without even looking it up because I've done a lot of sub research today, and not once did I take the time to look on truly how it binds and interacts with other opiods on the receptors, I figured I would always go by the weird logic that it actually kicks other binding agonist out of the way
 
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Yes someone explained that to him in the other section; he told him that once something binds to a receptor it is active as long as it is there on the receptor, rather then work in cycles, I don't know if your getting at the same thing though? Maybe just in diff words?

Actually nvm ur talking about on just how it works lol

BUT ur also stating that regular full agonist become bound to receptor(s) and work by constantly binding and dissociating? ?- and something like bupe actually will bind as well, but outcompete it's host pretty much? Lol So I'm assuming since it doesn't knock it off (because I never understood how it would just knock it off anyway, strong or not) would it bind and barley disssociate unlike its competitor? And is that how it outcompetes and eventually takes over? Or am I completely off track on this one?? Ahhaha

I do ask with confusion, but confidence lol because if it doesn't knock it off and if it doesn't outcompete obviously by just hanging on longer (since PWD happens quick) , I'm assuming the only possibility is that the bupe literally joins on (latches/binds) and either slowly cycles, or just latches on and stays dormant, while the other agonist cycles in and out until there's no more room for it....

-also I'd love to know why without even looking it up because I've done a lot of sub research today, and not once did I take the time to look on truly how it binds and interacts with other opiods on the receptors, I figured I would always go by the weird logic that it actually kicks other binding agonist out of the way

It's a competitive interaction. In a sense, bupe is a competitive antagonist of full agonists if the full agonist has a lower binding affinity. Chemistry is weird though, and you can't really think of molecular interactions like anything we're used to encountering/observing in our everyday lives.

I'll rephrase what i said in my previous post to try to clarify it a bit better, but the drugs never really "attach" to the receptor. They're almost instantaneously and constantly binding and dissociating, binding and dissociating, binding and dissociating, etc. That's just how rapid equilibria work. Buprenorphine's drug-receptor complex probably is more energetically favorable, so the receptor-drug interaction will naturally favor that over a full agonist which has to overcome a more substantial energetic barrier to bind the receptor. I'm trying to explain this in not technical terms, but you're asking a very technical question so my apologies if I'm only confusing you more 8(

In sum, unless there is an irreversible conformational change, drugs are always, and almost instantaneously, binding and dissociating from the receptor. If a drug has a more energetically favorable interaction at the orthosteric binding site, then that drug will have a higher binding affinity. Drugs with higher binding affinities will outcompete drugs with lower binding affinities. Binding affinity is inversely proportional to Kd (dissociation constant).
 
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