Neuroscience Researchers Discover Allosteric Site That Produces Analgesia If An Opioid Antagonist Is Consumed.

[4DQSAR]

Sci-Net: Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia

In this case BPRMU191 (the candidate) is:
4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid
CAS 2131199-53-2

https://www.medchemexpress.com/cas/2131199-52-3.html

A µ-opioid receptor modulator that works cooperatively with naloxone - Nature

A newly discovered negative allosteric modulator of the µ-opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.

www.nature.com

In this case, compound 368 (the candidate) is:
1-methyl-9H-pyrido[3, 4-b]indol-7-ol (Harmol). CAS 487-03-6

https://www.tcichemicals.com/GB/en/p/H1360

Now note that these papers are based on in-silico and in-vitro animal models of pain. It in no way set out to test if the combination of an opioid antagonist with one of those candidates is subjectively similar to a 'classic' opioid agonist. They only ever tested the analgesic activity.

To the best of my knowledge no human trials have been undertaken much less even animal models of toxicology. So do not assume that these offer some magic way to make a cocktail of naltraxone + a candiate will be in any way similar to oxymorphone.

I feel the most valuble thing is that allosteric sites have been identified. This potentially offers a way for someone who is physically dependent on a 'classic' opioid to carefully taper using what are currently considered to be antagonists. But that is merely a potential. It's far too early to start discussing it's use in such situations.

But it DOES offer an interesting question. If, consumed alone those candidates are not in themselves psychoactive, how would a legal definition be phrased? Because even the UKs NPS laws would not cover such a compound. But again, this it my speculating and it may turn out that in man both candidates prove not to be useful and/or practical and/or safe.

But they are interesting. The identification of the site is of more interest than any specific candidate.

 

[tuppingtoncity]

But it DOES offer an interesting question. If, consumed alone those candidates are not in themselves psychoactive, how would a legal definition be phrased? Because even the UKs NPS laws would not cover such a compound. But again, this it my speculating and it may turn out that in man both candidates prove not to be useful and/or practical and/or safe.

If the allosteric modulator + antagonist do actually produce typical agonist like effects and are actually used by people (prob not that likely), I fear that opiophobia knows no bounds and lawmakers (especially British and American ones) would find some way to weasel the combination into the prohibition framework.

But also pretty cool stuff pharmacologically speaking, I really wonder if the allosteric modulator + antagonist combination would produce effects similar to some partial agonists?

 

[MedicinalUser247]

Sci-Net: Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia

In this case BPRMU191 (the candidate) is:
4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid
CAS 2131199-53-2

https://www.medchemexpress.com/cas/2131199-52-3.html

A µ-opioid receptor modulator that works cooperatively with naloxone - Nature

A newly discovered negative allosteric modulator of the µ-opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.

www.nature.com

In this case, compound 368 (the candidate) is:
1-methyl-9H-pyrido[3, 4-b]indol-7-ol (Harmol). CAS 487-03-6

https://www.tcichemicals.com/GB/en/p/H1360

Now note that these papers are based on in-silico and in-vitro animal models of pain. It in no way set out to test if the combination of an opioid antagonist with one of those candidates is subjectively similar to a 'classic' opioid agonist. They only ever tested the analgesic activity.

To the best of my knowledge no human trials have been undertaken much less even animal models of toxicology. So do not assume that these offer some magic way to make a cocktail of naltraxone + a candiate will be in any way similar to oxymorphone.

I feel the most valuble thing is that allosteric sites have been identified. This potentially offers a way for someone who is physically dependent on a 'classic' opioid to carefully taper using what are currently considered to be antagonists. But that is merely a potential. It's far too early to start discussing it's use in such situations.

But it DOES offer an interesting question. If, consumed alone those candidates are not in themselves psychoactive, how would a legal definition be phrased? Because even the UKs NPS laws would not cover such a compound. But again, this it my speculating and it may turn out that in man both candidates prove not to be useful and/or practical and/or safe.

But they are interesting. The identification of the site is of more interest than any specific candidate.

This is great info to share with us. Thank You.

 

[Allylbenzene]

Quote from the paper:

We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling.
...
The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone

I wonder how TLR4 fits into all this. The study used naloxone which blocks TLR4 which in turn is known to reduce opioid tolerance and side-effects. It's possible that the opioid NAM modulates TLR4 also.

Blockade of TLR4 activation by its antagonists alleviate neuropathic pain.
...
We hypothesized that opioid antagonists such as naloxone and naltrexone, which were also demonstrated to be TLR4 antagonist, may have clinic application value in attenuation of opioid-induced hyperalgesia and tolerance.

— 10.1016/j.mehy.2012.08.021

Blockade of TLR2 and TLR4 produced analgesia and enhanced buprenorphine's effectiveness, which suggests that they may be a putative target for future pharmacological pain relief tools, especially for opioid rotation, when the effect of morphine is tolerated.

— 10.1155/2016/5238730

Opioid receptor agonists induce the production of high mobility group box 1 (HMGB1), an endogenous TLR4 agonist, supporting intercellular (neuron-to-glia or glia-to-neuron) interactions.
...
The DAMP HMGB1 is associated with the development of neuropathic pain.

— 10.3389/fimmu.2020.01455

In conclusion, TAP2 could effectively attenuate MIA-induced arthritis in rats by blocking TLR4 and its successive inflammatory cytokines and MMP13. Therefore, TAP2 could be a prospective therapeutic to treat patients with osteoarthritis.

— 10.1038/s41598-020-74544-5

There's more info on opioid-TLR4 dynamics in this post.

 

[MedicinalUser247]

So... Are these Opiates that can't be reversed by Narcan ?

 

[4DQSAR]

Nobody knows at this point. It's fine to form a hypothesis but for it to become a theory, one much have a weight of evidence. For it considered to be an axiom it must be able to predict if future evidence that supports the case.

Don't forget, no experiment can ever prove a statment to be TRUE, an experiment can only prove to be FALSE. Karl Popper details this and it is a formal part of the scientific process. Axioms are not, in fact, axiomatic. Newtows theory gravity is adequate in all but edge cases yet Einstien's space-time model not only equally covers all cases described by Newton AND the edge cases where gravity bends light, for example.

I used Einstein because it's a rare example of an extraordinary statment that required extraordinary evidence. In his lifetime, Einstein was repeatedly castigated for being wrong UNTIL astronomers using the light from the sun and the gravity of the planets to show that Einstein's calculations gave the precice results, his theory stated, thus Newtownian gravity is now useful for the purposes of most calculations, but is an estimation, not an axiom.

At the time a hundred physicists wrote an open later claiming that Einstein was wrong. When he was told, Einstein's reply was simple - 'If it's wrong, why did it need a hundred? One is sufficient'.

As we now know, that same theory was able to predict things that even now we lack the technology to test, but over the decades, it has predicted a large range of natural phenomina. THAT is what I mean by extrordinary evidence. That ability to predict cases.

 

[Allylbenzene]

Nobody knows at this point.

Agreed, as much as I think TLR4 is involved many undiscovered elements are at play.

Einstien's space-time model not only equally covers all cases described by Newton AND the edge cases where gravity bends light, for example.

What I've come to realise is that Maxwells equations which Einstein orientated his work on are incomplete. Thus the Einstein paradigm is also. But this is another discussion all together.

Spoiler: Einstein issues

There appears to be a few issues with Einsteins work. This person is better qualified to explain this than me, around ¼ down the page:

One problem I grappled with was my perception of serious errors and omissions in Einstein's relativity. Prominent physicists saw the same in the early 1900’s, but were ignored, so having productive conversations with physicists is more unlikely today than ever. Those in the mainstream will muffle their ears and block further discussion.
Entertaining thoughts that question Einstein will cost them their jobs. Critics are written off as crackpots. Many have been, unfortunately. The few who weren’t had nobody to talk to. But if science is to ever emerge from this last age of darkness, Einstein’s complicated theories and the awkward balloons and rubber mats used to explain them must be chucked and replaced with a logically sound, consistent comprehension of the essential relation between clock speed and gravity.

Further insights:

It amazes me that physicists have never focused on the existence of two dimensions, a necessary assumption for them having themselves conjured the notion of cosmic expansion. Some explain it as expanding space between galaxies, but not atoms, while others get it right. If the universe as a whole expands, so does everything inside. You can’t say there is such a thing unless a dimension outside the universe exists, but you’ll never hear a physicist mention it. This upper dimension I frequently refer to as the ethereal realm or upper land. I may not make a clear distinction between the infinite ethereal realm and the current volume annexed by the expansion of the physical universe for billions of years at the accelerated rate of c squared. Sometimes I think the failure of physicists to see the universe correctly is the inability of their minds to comprehend large numbers or outer boundaries. These concepts are going to be new to you then, too, so I’ve hopefully met the challenge of persuading you by carefully constructing a proof in the following pages so that you see it for yourself. I can’t believe I’m the first to see it, but the dogma of relativity and prospect of looking for another job keeps the light from penetrating.

This person is one of many but he was the first that came up in my search.

 

[4DQSAR]

Sci-Net: Activation mechanism of the μ-opioid receptor by an allosteric modulator

https://www.science.org/doi/10.1126/sciadv.aea9832

Sci-Hub. Positive allosteric modulators of the μ‐opioid receptor: a novel approach for future pain medications / British Journal of Pharmacology, 2014

Sci-Hub. A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects / Neuropharmacology, 2021

Sci-Hub. Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics / ACS Chemical Neuroscience, 2017

Sci-Net: Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor

Untangling the complexity of opioid receptor function - Neuropsychopharmacology

Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970’s, there have been major advances...

www.nature.com

Frontiers | Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo

Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properti...

www.frontiersin.org

Negative allosteric modulation of the µ-opioid receptor

The µ-opioid receptor (µOR) is a well-established target for analgesia, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression, which have led to the present opioid overdose epidemic. µOR negative allosteric modulators (NAMs) may...

www.biorxiv.org

Each paper cites around thirty earlier works but there is a lot of overlap. An AI using the whole set of references as it's sole dataset may well prove a valuable tool, but there is truth in that age old problem with all software. GIGO.

 

[Allylbenzene]

Anyway - this is a thread devoted to the possibility of a newly discovered allosteric site within the MOR receptor domain. I simply used that one case as an examplar. If you wish to focus on physics...

My response was to your use of that case re Einstein. I was pointing out it's unsuitability since Einstein was likely a fraud amongst other things - but regardless, I get what you were trying to convey with it.

I'm please you are so facinated by the Toll-Like receptors but this is a totally different site within a known domain. AI is infamous for simply geared to finding associations that please the user, not to actually provide them with objective data.

I'm old fashioned enough not to use those tools.

Anyway, as I wrote - as much as I think TLR4 is involved (or it's downstream elements) many undiscovered elements are likely at play.

 

[notsmokeymcpot42088]

Sounds like the beginning of a beautiful relationship....

Speaking of which in Einsteins book about the theory of relatively he only thanks one guy that died (research partner) with a very strange. "Michele left this strange world a bit before me. This makes no difference." -- A.E, Only a math guy would be either that cold or that invested in block theory.
(I do hope its called block theory now - I suspect even if not ya'll will get it)

Thats good stuff 100 physicists wrote in, "if its wrong, only takes one" (And a third person that understands?) ... Still think its crazy simpsons got that close to predicting the formula for the 'god' particle in the mid-late 90s on the episode intro

 

[4DQSAR]

Anyway, as I wrote - as much as I think TLR4 is involved (or it's downstream elements) many undiscovered elements are likely at play.

Fine. Read that second tranche of references - you may be in for a nice surprise.

In response to you single link:

Some random saying 'This is fraud' should be treated with the same skepticism as every other source. The citations aren't in an appropriate format. Citations should appear at the end of a sentence before the final punctuation, or within parentheses, not just as a block at the end. A whole book is NOT a citation. It's a source, but not a citation. This is conformation bias on your part.

Also, obstification is being employed as almost all of the books are out of print. So it's impossible for the reader to actually check if what is being quoted is what was written. Even those that are, the writer is employing the 'appeal to authoity' logical fallacy. It's assuming that the reader is a German speaker. Cherry picking is often a feature commonly found in pseudoscience. There are tens of thousands of academic papers based on the work of Einstein. That fact is not addressed.

Don't forget, in 1905 almost all physicists worked in isolation. Einstein was a 3rd class (lowest) 'technical expert' working the Swiss patent office. There were few journals and those only available to instututions. Einstein submitted to Annalen der Physik not because he had access to every issue, but because it was the only journal that fitted his paper. Personal communication was limited to meeting others, attending lectures given by others or exchange of letters. The first two were beyond his finanical resources at the time, Bern was only practically in reach of ETH Zurich, which only later became a significant hub of physics. the letters are found in Albert Einstein's letters, housed primarily at the Albert Einstein Archives at the Hebrew University of Jerusalem. In which he credits others. A PRIMARY source totally omitted.

An academic work should be open to criticism, the linked article is relying on it being impossible for anyone to critique. So stating based on ONE source that someone is 'likely a fraud' demonstrates that second voice bias. The scientific method embraces the use of earlier works, it's the reframing and usage of them that is what allows progress. Einstein was able to remove the concept of a 'univeral ether' which had plagued physics for centuries. Again, not addressed. While Einstein used Lorentz transformations (Hendrik Lorentz and Henri Poincaré ideas), he was the first to realize their physical meaning, stating that relativity was a universal principle, not just a mathematical trick. He also included a footnote at the bottom of the appropriate page crediting Lorentz and Poincare.

What it does do is kind of gloss over the fact that Einstein predicted gravitational lensing, gravitational waves and black holes. Still more predictions have yet to be tested. So 'likely' is not a rational metric. As time goes on, more predications will likely become testable, so we can both look and see if those predictions turn out to be right or wrong.

"Extraordinary claims require extraordinary evidence" (ECREE), often termed the 'Sagan standard' is recognized. Cold fusion would be an example of a claim without such evidence... and we all know how that panned out.

I shouldn't need to have to point these things out to you. It's the scientific method. If you seek to reject the scientific method, at least say so.

Thesis, antithesis, synthesis.

By all means start a thread. But this one is about the apparent discovery of an allosteric site within the domain of the MOR receptor.

 

[4DQSAR]

Sci-Hub. Allostery at opioid receptors: modulation with small molecule ligands / British Journal of Pharmacology, 2017

Ignore the title - it's a link to the paper.

BMS-986122 | µ-Opioid Receptor Positive Allosteric Modulator | MedChemExpress

BMS-986122 is a selective, potent positive allosteric modulator of the mu-opioid receptor (µ-OR). BMS-986122 shows potentiation of orthosteric agonist-mediated β-arrestin recruitment, adenylyl cyclase inhibition, and G protein activation. BMS-986122 potentiates DAMGO-mediated [35S]GTPγS binding...

www.medchemexpress.com

Intracellular/Lateral Site (BMS-986122) is of particular interest. References suggest it to be a primary allosteric site. It was identified using BMS-986122 which located a lateral pocket involving transmembrane helices TM3, TM4, and TM5.

Now what is interesting is that in my first post, BPRMU191 offers us the possibility of using synthetic 18F (radiofluorine). While it's half-life is only around 100 minutes, it does offer the possibility of functional MRI as a methodology of watching in realtime how the ligand crosses into the brain and test if it is selective and if the regions of the brain noted have a slightly different MOR domain.

I mention this only because BMS-986122 doesn't offer that possibility. But it is structurally very similar. It seems possible that one role of the sulfonyl moiety is to prevent axial rotation of the aromatics. Essentially performing the same role as the 2-methyl moiety found in the structure of BPRMU191.

 

[4DQSAR]

Sci-Hub. Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators / Journal of Computer-Aided Molecular Design, 2020

I feel this has value not so much for the computation but the fact that it visualizes the MOR receptor domain.

It took decades of research to confirm that the ORL1 (NOP receptor) was a similar but different to the MOR receptor. In fact it took decades for the sigma receptor to be removed from the list of known opiate receptors. These things generally require many researchers to confirm that so far, every experiment concluded that it was indeed a seperate receptor.

I can throw up links but I hope people are capable of finding appropriate papers on the NOP receptor if they really wish to follow the path to it's formal identification.

 

[MedicinalUser247]

I would love to work with Computer Aided programing. It would make drug designs without even needing to think about what goes where to hit the correct receptors. I can just imagine what it would be like.

 

[4DQSAR]

I would love to work with Computer Aided programing. It would make drug designs without even needing to think about what goes where to hit the correct receptors. I can just imagine what it would be like.

Well, Avagardo is free and open-source. There are a range of plug-ins. I don't know all of them, but since it IS open source, it's quite likely someone will have a plug-in to suit your needs.

 

[4DQSAR]

Sci-Hub. Interplay between Two Allosteric Sites and Their Influence on Agonist Binding in Human μ Opioid Receptor / Journal of Chemical Information and Modeling, 2016

It bugged me that two seemingly unrelated classes of compound were identified as MOR allosteric modulators. So here we are, there are TWO allosteric sites, or at least, this is what experiments consistantly suggest.

I think it's also important to note that researchers long ago recognized that it was the flow of Na+ ions that actually 'drove' the MOR receptor's output. So you may have noted that thousands of papers that used in vitro models tested their novel MOR ligands with Na+ ions and without - and just how different the results were.

 

[Allylbenzene]

Posting this here instead of creating a new thread:

A µ-opioid receptor superagonist analgesic with minimal adverse effects

A µ-opioid receptor superagonist analgesic with minimal adverse effects - Nature

N-desethyl-fluornitrazene is a µ-opioid receptor agonist derived from nitazenes that has supramaximal intrinsic efficacy that produces analgesia with minimal adverse effects in rodent models.

doi.org

 

[4DQSAR]

Could it be something similar to NFEPP? That the ligand primarily acts on peripheral opiate receptors? In the case of NFEPP, the pKa means that at physiological pH, it's charged so cannot cross the BBB. Clever trick, in my opinion as at once, it may also act as a bioisostere of a methyl group and we know that 3-methyl fentanyl is a lot more potent than plain vanilla fentanyl so one atom, to major changes in activity?

Or maybe it's biased?

https://www.mdpi.com/1422-0067/26/5/1862

We know from primate models that biased ligands at sufficent doses will still produce both addiction and physical dependence. But the more biased, the less that seems to happen. I can recall a critique of one biased ligand in which the author noted that the experiments could equally be explained by it being a high-affinity, low-effacacy ligand. Sort of a partial agonist. There was qute a bit of back-and-forth on that one topic.

I didn't read it all as it occured to me that be it a partial agonist, mixed agonist or low effacacy ligand, the real world results would be much the same. Less abuse potential, less dependence liability and a reasonable stepping-stone for detoxification.

We have two licenced biased MOR ligands in use now. Oliceridine (Olinvyk™) and TVR734 (Tegileridine™) which we can read the human cohort studies of both:

Oliceridine for postoperative pain and opioid-related complications: The intravenous oliceridine and opioid-related complications (VOLITION) prospective cohort study - PubMed

Nearly one quarter of patients experienced a respiratory compromise with oliceridine analgesia, none of which was life-threatening. A randomized trial needs to determine whether oliceridine produces fewer overall ORAEs than conventional opioids. The study was registered at ClinicalTrials.gov...

pubmed.ncbi.nlm.nih.gov

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00550-6

And a comparison of the two:

https://www.tandfonline.com/doi/full/10.2147/DDDT.S565369#d1e298

I've only provided one paper on each, but there are many, so anyone interested can use Google Scholar. If it's behind a paywall, I will do my best to get them for anyone who asks.

 

[Skorpio]

Posting this here instead of creating a new thread:

A µ-opioid receptor superagonist analgesic with minimal adverse effects

A µ-opioid receptor superagonist analgesic with minimal adverse effects - Nature

N-desethyl-fluornitrazene is a µ-opioid receptor agonist derived from nitazenes that has supramaximal intrinsic efficacy that produces analgesia with minimal adverse effects in rodent models.

doi.org

This paper (open access) is a banger. Except for that one R/opiatesItaly citation in the discussion.

Could it be something similar to NFEPP? That the ligand primarily acts on peripheral opiate receptors? In the case of NFEPP, the pKa means that at physiological pH, it's charged so cannot cross the BBB. Clever trick, in my opinion as at once, it may also act as a bioisostere of a methyl group and we know that 3-methyl fentanyl is a lot more potent than plain vanilla fentanyl so one atom, to major changes in activity?

Or maybe it's biased?

The paper claims that their nitazene binds mu receptors on their own quite well, but heterodimers of galanin receptors and mu receptors have a lower binding affinity.

They compare it to esmethadone which apparently has a similar lack of binding to mu-gal heteromers.

In general they were pretty thorough in comparing a lot of the additiveness aspects (as well as measuring hypoxia) in addition to measuring the analgesic potential.

However, with all “less addictive opioids” we shall certainly see.

Also one thing that kind of gives me the heebie jeebies is that fluoroethyl group. Hope it doesn’t make fluoroacetate and slowly poison the tca cycle of long term users.

 

[4DQSAR]

@Skorpio - it seems that it matters not just how a psychaitric drug alters mood and/or perception. At least some people will take them!

I honestly wonder if that -F screws up the pKa so yes, potent ANALGESIC in animal models, but as you say, toxicity isn't an issue if the ligand is purely to elucidate the receptor domain (18F) but we know that pheripheral MOR receptors ARE important. Battlefield medicine states that 'red tops' (morphine or such) are injected into muscle above the wound in cases of a limb injury and near the site of injury if it's the body.

I have no idea just how effective M is in it's periperal role, but if this novel compound works by biasing towards peripheral receptors BUT still providing a small amount to bind with cental receptors, that would be less addictive, I suppose. But never underestimate what crazy things people will do. Loperamide FFS!