Biased agonism: a real phenomenon, an over-used explanation

Posting this under the heading it deserves: Biased agonism: a real phenomenon, an over-used explanation Everything below is what sits behind that.

Trying to work out what would count as evidence on biased agonism, before collecting any. This is the part I usually skip and it is the part that makes the rest useful.

If two explanations predict the same observation, observing it does not help. So: what observation would separate them?

Receptor desensitisation and internalisation are real phenomena in vitro and their clinical relevance to these compounds is not established. That distinction gets lost in discussions about tolerance.

What I would want before treating biased agonism as settled: the method, the sample, and whether anyone tried to find the opposite result. Two of the three are usually missing.

The arithmetic in post #44 is right; the assumption feeding it is the part to check.

GLP-1 receptor agonism produces its metabolic effects through more than one route: central satiety signalling, delayed gastric emptying, and glucose-dependent insulin secretion. Attributing everything to one of them is where most simplified accounts go wrong.

On reflection I would soften that slightly.

Worth separating two things that post #57 runs together.

Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.

I would not lead a decision with this, but I would not ignore it either.

The arithmetic in post #62 is right; the assumption feeding it is the part to check.

The most useful thing anyone has posted about biased agonism in this category was a table of what had been measured and by whom. That is what I would want again.

Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.

Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.

On post #105 — agreed on the reasoning, with one qualification.

Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.

That is what I would do. It may not be what is correct.