Pharmacology Reasons I suspect that extremely strong propioanilides & nitazenes are not very responsive to strong MOR antagonists & partial MOR agonists

[MobiusDick]

I'm not going to cite references today bc I got the COVID mRNA vaccine & 2nd Shingles Vax yesterday & my temp is ~ 104 F .
I've been thinking a lot about this as I have been sampling very strong fentanyl analogues like isocarfentanil, lofentanil, sufentanil, & betahydroxyalphamethylfentanyl, as well as the piperazine based benzimidazole based nitazenes like metonitazene, isonitazene, N-pyrrolidino metonitazene and etonitazene lately & while it seems that Etonitazene is one of the strongest, the piperazine group causes extremely high anticholinergic effects, or some other receptor that causes dry mouth as it seems this is the effect that is way off the chart in relation to any other opiods . But aside from that, there seems to be a disconnect between the effect these drugs have on MOR and the effect that they have on Beta-arrestin-2. I believe when this disconnect occurs, the cell internalizes the MOR to downregulate & unless you administer the MOR antagonist or partial agonist quickly, the internalized MORs are not as naloxone /buprenorphine labile or susceptible. My results are anecdotal and as many of you who are aware of my history from Alt.Drugs.Hard and so on, As the Beta-Arrestin-2 Ki levels show higher binding affinity as well as Ki MOR levels going into pM and fM range. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor much more quickly than the other fentanyl derivatives, but when given time, the same thing happens, so it may be that some of these drugs are weaker GRK2/3 inhibitors in their own right. So my criticism of this study involves perhaps an autooxidation or reduction

MobiusDick

Here is a reference for you to look at and as soon as I feel better I will explain why I feel this way and possible changes to the study to confirm or disprove my suspicions

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.16084

 

[vecktor]

Vintage poster welcome back!

The antagonist would also need pretty decent affinity to displace a potent agonist obviously if it iscompetitive, doesn't apply if it is irreversible or non competitive, The experiment is made more complex if the agonist stabilises the active conformation and this is unfavourable for antagonist binding. Something like carfentanyl is going to potently bind and drive the receptor internalisation, and I guess it essential remains bound even to the internalised receptor. The super potent agonist hard to displace mechanism I think is seen with Bentleys compounds like M99 and similar, they are simply not displaced by standard antagonists partial agonists, allegedly etonitazine is similar.

Not all the strong tachyphalaxis causing opioids, fentanyl itself shows tachyphalaxis IIRC, seem to be arrestin biased according to the study, Tachyphalaxis being a marker one would logically associate with internalisation and arrestin recruitment and rapid loss of surface receptor density. I would be interested to see data showing whether it is carfentanyl alone that is biased and what the other fentanyl family do, because my quick scan read of the the study showed they really only looked at fentanyl carfentanyl and DAMGO the reference to 'the fentanyls' means it seems more than 1 (actually 1 more than 1 fentanyl and carfentanyl for a total of 2)

There is discussion elsewhere in this sub formum on splice variants of mu, I remember you were the first to mention it a long long time ago, long before 2008 very interesting and something I knew nothing about at the time, so thank you for sharing. I would be interested to hear your current thoughts.

Good to hear you are still going, opioids are clearly not so dangerous, but maybe watch out for mRNA concoctions and heavily adjuvanted shingles potions.