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Neuroscience Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

This thread contains discussion about a Neuroscience-related topic
This is about as much information out there as I can find..


Mu1,2,3 receptors (MOR) bind to endogenous ligands - beta-endorphin, endomorphin 1 and 2 with proopiomelanocortin (POMC) being the precursor.

The mu-1 receptor is responsible for analgesia and dependence.

The mu-2 receptor is vital for euphoria, dependence, respiratory depression, miosis, decreased digestive tract motility/constipation

Mu-3 receptor causes vasodilation. Kappa receptors (KOR) bind to dynorphin A and B (Prodynorphin as the precursor). They provide analgesia, diuresis, and dysphoria.

Delta receptors (DOR) bind to enkephalins (precursor being Proenkephalin). They play a role in analgesia and reduction in gastric motility.

Nociceptin receptors (NOR) bind to nociceptin/orphanin FQ (Pre-pronociceptin is the precursor) causing analgesia and hyperalgesia (depending on the concentration).

Zeta receptors (ZOR) regulate developmental events in a variety of normal and tumorigenic tissues and cells.[1]


But there's a handful of sites that say otherwise, not sure which ones are the most correct or reliable. lol
 
DeathIndustrial88 said:
I find the idea that subreceptors are responsible for the varying intensity of euphoria & pleasant effects among opioids to be interesting.

For example, drugs like heroin supposedly bind to mu2, while drugs like fentanyl don't. So even though they're both mu-agonists, heroin feels better because it binds to mu1, mu2 and mu3. I dunno how true this is though. I've read some literature about it but can't find much of it anymore. Doesn't seem like they're really looking into subreceptors much. But if true, it would explain why all mu-agonists feel slightly different from each other (besides their binding profiles at delta & kappa).

But I've come across sites that also say it's mu3, so I have no idea. Anyone else know anything about subreceptors & why drugs like heroin are still more enjoyable than ultra potent agonists like the fentanyls? Seems like when it comes to opioids, the higher the potency, doesn't always equal better effects.
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Subreceptors definitely do influence effects to some extent.

Less potent opiates maybe detach from receptors and hit them again, something like that. That's one of countless possible reasons why H is much better than fent.
 
DeathIndustrial88 said:
The mu-2 receptor is vital for euphoria, dependence, respiratory depression, miosis, decreased digestive tract motility/constipation
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So it's mu-2 that is apparently responsible for euphoria? Now all we need to do is create an opioid agonist compound that agonizes that mu-2 subreceptor as much as possible without enhancing motility, respiratory depression, dependence, etc. and we're good lol. But you're saying that other reports contradict those findings, so it seems that still more research needs to be done.

See, if euphoria was seen as a legitimate antidepressant effect that opioids have, instead of a side effect, we would have a whole lot more research going on in this direction. We'd probably know by now what exactly it is that triggers the euphoric response and be able to synthesize opioids with a stronger euphoric potential, just like we are able to create opioids like fentanyl that have a stronger analgetic potential. In that case we could seperate opioids into two classes: pain treatment opioids and antidepressant opioids. Wouldn't that be wonderful?
 
Hexenstahl said:
So it's mu-2 that is apparently responsible for euphoria? Now all we need to do is create an opioid agonist compound that agonizes that mu-2 subreceptor as much as possible without enhancing motility, respiratory depression, dependence, etc. and we're good lol. But you're saying that other reports contradict those findings, so it seems that still more research needs to be done.

See, if euphoria was seen as a legitimate antidepressant effect that opioids have, instead of a side effect, we would have a whole lot more research going on in this direction. We'd probably know by now what exactly it is that triggers the euphoric response and be able to synthesize opioids with a stronger euphoric potential, just like we are able to create opioids like fentanyl that have a stronger analgetic potential. In that case we could seperate opioids into two classes: pain treatment opioids and antidepressant opioids. Wouldn't that be wonderful?
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That would be amazing!
More research definitely should be done here.


Some one on here awhile back told me that they haven't cloned the subreceptors or something like that. But I don't know how they would have any of this information if they hadn't cloned them or tested them in a lab some how. Although the lack of information surrounding subreceptors makes me wonder.

It's sounds reasonable though that they play a significant role in the subjective effects of opioids.
Especially since it can't just be chalked up to general mu-agonism when highly potent drugs like fentanyl & buprenorphine can't even a hold a candle to stuff like heroin. If it was just general mu agonism that caused euphoria, then bupe & fentanyl would be incredibly euphoric.

I think it's unfortunate that euphoria & "feelings of wellbeing" are considered unwanted side effects. Actually I think it's utterly ridiculous. Why shouldn't some one have the right to feeling well or euphoric? Who's property is my brain & neurochemicals other than mine? Those "side effects" are absolutely welcomed by people who feel like shit every day.
 
DeathIndustrial88 said:
think it's unfortunate that euphoria & "feelings of wellbeing" are considered unwanted side effects. Actually I think it's utterly ridiculous. Why shouldn't some one have the right to feeling well or euphoric? Who's property is my brain & neurochemicals other than mine? Those "side effects" are absolutely welcomed by people who feel like shit every day.
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Couldn't have said this better myself!
 
Hexenstahl said:
I find the subreceptor theory interesting too. Haven't given it much thought though.

Regarding your last paragraph: higher potency rarely equals to a stronger euphoric response because the analgetic potency seems to work through a different mechanism. I don't know much about that though...
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No, I mean that reference which gives purity also has a GC-MS of the sample so you can cut up the molecule into fragments in something like ChemSketch and look at the MW of the fragments.

There are fragments in that GC-MS that clearly don't come from the compound it's supposed to be so it's possible, with reference to the synthesis, to work out what the impurities likely are. It's a dull, dull, dull process but it's how you work out what is in the sample.
 
DeathIndustrial88 said:
Mu1,2,3 receptors (MOR) bind to endogenous ligands - beta-endorphin, endomorphin 1 and 2 with proopiomelanocortin (POMC) being the precursor.
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This feels odd. I am proximal to a neuroscience department that does a lot of work on addiction, and I have never seen these mu receptor subtypes discussed, where I have seen functional selectivity and other nuances discussed.

Also, there aren't a lot of primary sources for mu1, mu2, and mu3 receptors after the mid 90s, where these receptors were defined as populations activated by different peptides.

Finding structural or genetic evidence for different splice varients of the mu receptors would convince me of this (and I'll try rewording my searches), but it kind of feels like people have moved on from that hypothesis due to the lack of current work building off of it.

Edit for more info: I wonder if these subtypes represent splice varients or maybe unique heterodimers with different receptors (delta-mu heterodimers are well known). These subtypes were all defined by differences in binding affinity of different opioid peptides, so there is something going on, I just wonder if that difference in binding has been explained by a more current model, or even if it's due to pharmacokinetic differences in the peptides themselves. I wanted to add this edit, because the use and then disuse of these terms is interesting to me, as there feels like an unspoken story there.

In general, one of the difficulties of the scientific literature is when one model gets subsumed by another. You can often tell this happened when can see papers stop referencing a model completely over time, especially in as active a field as opioid signaling.
 
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Morphine, diacetylmorphine, and desomorphine are the best IV opioids

Oxycodone is probably the best oral opioid
 
Skorpio said:
This feels odd. I am proximal to a neuroscience department that does a lot of work on addiction, and I have never seen these mu receptor subtypes discussed, where I have seen functional selectivity and other nuances discussed.

Also, there aren't a lot of primary sources for mu1, mu2, and mu3 receptors after the mid 90s, where these receptors were defined as populations activated by different peptides.

Finding structural or genetic evidence for different splice varients of the mu receptors would convince me of this (and I'll try rewording my searches), but it kind of feels like people have moved on from that hypothesis due to the lack of current work building off of it.

Edit for more info: I wonder if these subtypes represent splice varients or maybe unique heterodimers with different receptors (delta-mu heterodimers are well known). These subtypes were all defined by differences in binding affinity of different opioid peptides, so there is something going on, I just wonder if that difference in binding has been explained by a more current model, or even if it's due to pharmacokinetic differences in the peptides themselves. I wanted to add this edit, because the use and then disuse of these terms is interesting to me, as there feels like an unspoken story there.

In general, one of the difficulties of the scientific literature is when one model gets subsumed by another. You can often tell this happened when can see papers stop referencing a model completely over time, especially in as active a field as opioid signaling.
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Are there any sources discussing the primary sequence of splice variants or is it all based on drug response?
 
COST.

Until 2006 hydromorphone had to be made by reducing morphine to dihydromorphine and then oxidizing it to hydromorphone. The yields of the two steps have incrementally improved over the decades but was still only about 60% overall. There was a direct route but the patent vastly overstated the yield which was calculated BRSM and not by product. In truth, hydromorphinone was the main product.

So the cost of an equipotent dose of morphine or diamorphine was lower. In addition, it's better to stick to the 'gold standard' (morphine) and it has the longest history of use and so doctors are more comfortable using it.

Most nations no longer use diamorphine because it depresses breathing more than morphine.

But in 2014 a certain 'David X Wang' was named as inventor in a patent in which morphine is rearranged directly to hydromorphone in one step and in >97% yield. Now, I don't know if the makers of hydromorphone have chosen to pay a licence to use the new synthesis but I imagine anyone in a nation where H is produced is unlikely to be concerned that they are in breach of patent law so I'm CERTAIN chemistry students at Kabul University and Naypyidaw State Academy are watching closely.

It may still take a while for someone to find a simpler catalyst (Wang used RhCl(P(C6H5)3)3 AKA Wilkinson's catalyst) BUT because of it's high price (and high MW meaning you need a lot), their is a LOT of research going into finding cheaper alternatives. Replacements for specific reactions are being found all the time but so far nobody appears to have on that rearranges a 2-cyclohexenol to a cyclohexone still uses costly catalysts BUT because of it's commercial value, people ARE looking.
 
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@Hexenstahl I read some of your texts here and there, they could be yours as well as copy&paste but even if it's just stuff you studied and remember and write down with words you learnt, what studies did you accomplish? Your English is also quite good.
 
wirkdy said:
@Hexenstahl I read some of your texts here and there, they could be yours as well as copy&paste but even if it's just stuff you studied and remember and write down with words you learnt, what studies did you accomplish? Your English is also quite good.
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Are you asking what I have studied in University?
 
AlsoTapered said:
COST.

Until 2006 hydromorphone had to be made by reducing morphine to dihydromorphine and then oxidizing it to hydromorphone. The yields of the two steps have incrementally improved over the decades but was still only about 60% overall. There was a direct route but the patent vastly overstated the yield which was calculated BRSM and not by product. In truth, hydromorphinone was the main product.

So the cost of an equipotent dose of morphine or diamorphine was lower. In addition, it's better to stick to the 'gold standard' (morphine) and it has the longest history of use and so doctors are more comfortable using it.

Most nations no longer use diamorphine because it depresses breathing more than morphine.

But in 2014 a certain 'David X Wang' was named as inventor in a patent in which morphine is rearranged directly to hydromorphone in one step and in >97% yield. Now, I don't know if the makers of hydromorphone have chosen to pay a licence to use the new synthesis but I imagine anyone in a nation where H is produced is unlikely to be concerned that they are in breach of patent law so I'm CERTAIN chemistry students at Kabul University and Naypyidaw State Academy are watching closely.

It may still take a while for someone to find a simpler catalyst (Wang used RhCl(P(C6H5)3)3 AKA Wilkinson's catalyst) BUT because of it's high price (and high MW meaning you need a lot), their is a LOT of research going into finding cheaper alternatives. Replacements for specific reactions are being found all the time but so far nobody appears to have on that rearranges a 2-cyclohexenol to a cyclohexone still uses costly catalysts BUT because of it's commercial value, people ARE looking.
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2 mg hydromorphone = 5 mg diamorphine = 10 mg morphine for equipotent analgesia. Morphine had the highest rating for euphoria. Only 17 out of 75 hydromorphone users reported euphoria (22.6%), meanwhile, 32 out of 41 morphine users reported euphoria (78%) and 29 out of 43 diamorphine users reported euphoria (67.4%.)
 
wirkdy said:
I don't know if you went to uni, studies in general, autodidact, whatever, if uni then so.
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Formally I studied Finance in University (Bachelors degree), but the little bit of knowledge that I have in other areas is something I have learned and am still learning autodidactically. Why are you asking?
 
Hexenstahl said:
Formally I studied Finance in University (Bachelors degree), but the little bit of knowledge that I have in other areas is something I have learned and am still learning autodidactically. Why are you asking?
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Oh nothing special really you know, just finalizing our marriage. How about next Tuesday at 11:15?
ps. sorry I had to spoil the surprise!!
 
kokaino said:
2 mg hydromorphone = 5 mg diamorphine = 10 mg morphine for equipotent analgesia. Morphine had the highest rating for euphoria. Only 17 out of 75 hydromorphone users reported euphoria (22.6%), meanwhile, 32 out of 41 morphine users reported euphoria (78%) and 29 out of 43 diamorphine users reported euphoria (67.4%.)
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Everyone is different - those figures are only rough guides and are subject to a multitude of variables .Some people experience little not no analgesia let alone euphoria from ANY of those drugs - specifically people who have a genetic mutation that result in phenolic opioids being metabolized and excreted extremely quickly.

That's why EVERY nation ensures it uses at least one non-phenolic opioid for severe pain. Be it oxycodone, methadone or even sustained release formulations of fentanyl. It's from clinical necceccity.
 
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