picomolar affinity opioid

[Neithman]

Well ive read an article on a kappa agnist used as an analgetic https://en.wikipedia.org/wiki/Nalfurafine

And apparently it has picomolar binding affinity to Kappa Opioid Receptors(1000 picomolar=1nanomolar)which is insanely high
I know affinity is everything ut it does a big role in how potent effects are,atleast when you have standartized testing system which confirms the high ow low binding of a substance.


My questio now is,would it be possible to design a MU binding opioid wih picomolar binding and also high intrinsic activity with a favourable inding profible that makes it euphoric,because fentanyl has very high inding affinitys and while it very strog and tends to induce tachykardia very fast,its regarded as not very euphoric
Is such high binding limited to very potent substances(potent in terms of potency per mg) because lofentanyl and other highly potent fentanyl analogues also have higher binding affinitys than fentanyl.

Is this just a coincidence or does a opioid has to be very potent to also have extremely high binding affinities,or is it possible to design a compund with morphine like potency with similar or even higher(picomolar) binding affinity than fentanyl

Imagine a morphine,thebaine analogue with picomolar affinity,high instrinsic activity and very high lipid solubillity and long duration
I guess it would not only be the most euphoric opioid known to man,but would make you almost immune to other opioids(which carfentanyl and such already kinda does)but given enough access and also having a substance with long duration this wouldnt be so much of a problem.

 

[sekio]

would it be possible to design a MU binding opioid wih picomolar binding and also high intrinsic activity [...] I guess it would not only be the most euphoric opioid known to man

Potency does not equal euphoric potential, unfortunately. Most opioid users will prefer heroin/morphine to fentanyl when given the choice even though fentanyl is "stronger".

Etorphine and its dihydro analog are approx. 1000x stronger than morphine, dihydroetorphine is used as a painkiller in China apparently, the dose is very very low though. But I don't see anyone abusing them.

Even the 3-methylfentanyl "epidemic" in Estonia and other former soviet bloc countries is just because people can't source opium/heroin, not because it's more enjoyable.

I think this is because morphine and friends have other activities (e.g. histamine releaser) that more selective mu-agonists lack.

 

[Neithman]

im aware of all of these facts,i even wrote myself that even though its high binding affinity,fentanyl istn that euphoric,which could be because of mu1 receptor selectivity,thats ehy i wrote a highly functionalized morphine,thebaine analogue with picomolar binding affinity and few extra features could do the trick

i find this topic insanely interesting,but such opioid will probably never pop on the market because of the fk FDA

 

[Limpet_Chicken]

The chinese use dihydroetorphine as we use methadone, the dose per tablet (that I know of, there may be other dose units) is 2ug. Quite surprising, considering the chinese. Surprising that is that they have evolved past just shooting people (and probably mixing them in with cheap noodles when they can't get the dog or cat [tongue in cheek, I've nothing against the chinese people, the government, definitely, bunch of wankers, but I have no prejudice against the chinese people themselves, although I can't say as I approve of the eating of cats by anybody, chinese or otherwise. The egyptians had the right idea in the feline department)

Fentanyl is selective for Mu1? interesting. I've tried a less potent Mu1 selective agonist (meptazinol, plus also either its propionyl or benzoyl ester, I forget which, made both ages back and ending up dumping one, after it too turned out to be shit. The esterification was following the same lines of thought as when salicylic acid was used to prepare aspirin, after meptazinol itself really did a number on my insides, causing severe GI pain.) Tried one of the two esters, and can't remember which, seeing as this was years back, and the project was discarded and judged to be a failed abortion that tried to crawl out of the flask that gave it birth, despite a kick in the stomach (it's, and mine both, the latter being responsible for the former)