G-protein biased mu opioid agonists: a wild goose chase?

[S.J.B.]

G-protein biased mu opioid agonists have been a hot topic in drug development for more than a decade, with some recent well-known drug candidates in this class including oliceridine and PZM21. The quest for these ligands was based on evidence that suggested that mu opioid agonists that could select for the G-protein signaling pathway over the alternate beta-arrestin pathway could demonstrate reduced respiratory depression and constipation relative to non-biased ligands. A new paper just came out, however, that seems to indicate that the main publication that kicked off all this R&D was in error. As summarized by Derek Lowe of In the Pipeline:

For at least ten years now, it’s been a popular hypothesis that the mu-opioid receptor might be splitting its effects via two different signaling pathways – the “standard” G-protein second-messenger one and the beta-arrestin pathway. That’s thought to be involved in receptor desensitization, among many other things, and there are a number of examples of differential signaling (and differentiation of side effects) depending on arrestin binding. There’s some evidence that you might be able to get analgesia without development of opioid tolerance and without smooth muscle effects if you could find ligands that activated the G-protein pathway and not the beta-arrestin one, and naturally enough there’s been a lot of work devoted to that idea. Compounds trying to put this idea to the test have recently made it far into clinical trials, but results have not been encouraging.

Comes now the cold water. A new paper demonstrates that in mice that have had their key beta-arrestin-2 protein completely knocked out that morphine and other opioid ligands still produce respiratory depression (and constipation, for that matter). This ties in with another recent paper (from some of the same authors) that looked at a series of mutant proteins that biased the mu-opioid receptor towards G-protein signaling and away from arrestin pathways, and that one showed that the heightened sensitivity to analgesia part might well be real, but that respiratory depression was still showing up and might even be worse.

So why hasn’t this experiment been run before? Well, that’s the thing: it has. In fact, the 2005 paper that really called attention to the possible therapeutic split in mu-opioid signaling was a demonstration in beta-arrestin-2 knockout mice (!) This latest paper, in fact, is a consortium across research teams in Germany, the UK, and Australia to re-examine this whole hypothesis due to all the conflicting results. They used the same knockout rodent line as in the 2005 work, but their results flatly contradict the earlier study, and they have no explanation for why this should be (although there’s a possibility that the earlier paper’s knockout animal strains were not sufficiently characterized). The paper also mentions a recent conference presentation from yet another group that has failed to reproduce the results as well.

The research paper was published last week in the British Journal of Pharmacology. Worth the read!

 

[Nagelfar]

Even so, "wild goose chases" are good for development overall. I wonder if personalized genetic metabolism will come to account. I already know I'm slow on both copies of CYP2D6

 

[sekio]

I thought arrestin was part of the whole tolerance development mechanism, do these opioids have reduced tolerance development?

 

[Nagelfar]

I thought arrestin was part of the whole tolerance development mechanism, do these opioids have reduced tolerance development?

Yes the Derek Lowe quote in OP goes into that. AFAIK results of splitting beta arrestin and G coupled protein have been disappointing.