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

[Skorpio]

@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!

They compare that compound to morphine in many of the experiments. Also I wouldn’t describe it as peripherally selective as much as selective against receptor complexes in the VTA.

 

[4DQSAR]

They compare that compound to morphine in many of the experiments. Also I wouldn’t describe it as peripherally selective as much as selective against receptor complexes in the VTA.

No, I simply mean that periperal activity of opioids was ignored or not understood for many decades. Then the protocol changed in that instead of 'any large muscle' to specifically close to the site of injury. It certainly appered to work in that battlefiled medicine is rough and ready but just for once, someone reassesed it's activity and that protocol was change (in quite a hurry).

I've always been cautious of animal models because they are so often wrong. Did you calculate the pKa of the ligand? I only have access to estimation tools;

The predicted pKa of etonitazene is 9.90 ± 0.25
The predicted pKa of N-desethyl etonetazine is 9.85 ± 0.19
The predicted pKa of fluetonitezine is 8.5 ± 1

I'm just wondering if that secondary amine being a HBD and the terminal -F being a (weak) HBA somehow alters that pKa.

Are mice commenly used when modelling the human brain for the purposes of MOR domains? It's been so long that when I touched this stuff, we got to play with microtomes BUT not with 18F tracers, sad to say.

I agree with the conclusion. It's context that matters. I know of a case in which someone who had bone cancer was on some tremendous amount of opioids to the point where they became toxic. So the patient ended up in hospital and after consultation with an anaesthetist, a syringe-driver containing sufentanil was use to control the pain. So they at least didn't die in agony.

The sudden opioid panic in the US saw the development of sufentanil patches abandoned. Yet the TI of sufentanil is ≈ 26,700, compared with 280 for fentanyl, 70 for morphine and 5 for pethidine.

I have a hypothesis that sufentanil is a duellist. Certainly swapping the N-methyl of morphine with a 2-(2-thienylethyl) moiety results in a compound that is less selective. So increased analgesia BUT mediated by acting on all of the opiate receptors. I checked my working by then looking at the 2-(2-furanylethyl) homologue and that appears totally unselective - so on paper, it may look attractive to an RC vendor, but my hypothesis is that the subjective effects will not be as euphoric, or at least any euhproia would only be experienced at dangerously high doses.

 

[4DQSAR]

An allosteric site within the NOP receptor domain is also known BUT they are not within the MOP receptor domain. Thusfar only JTC-801, J-113397 & AT-121 are believed to act in an allosteric (non-competitive) manner.

I think it worth reminding people that one of the nitazenes is not like the others. In animal models it was ≈ x6000 M in terms of analgesic potency. (S)-α-carboxamidoetonitazine. The increased potency is due to it acting on not only the MOP but also the NOP receptor domain. It is unclear if this compound a duelist OR if it acts as a competative ligand at the MOP and as an allosteric modulator at the NOP.

The appropriate patents and papers were uploaded to this site some time ago.

 

[4DQSAR]

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