Receptor desensitisation as a tolerance hypothesis, and its weak evidence posts 31–58

I read the earlier replies on receptor desensitisation twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.

I read post #28 twice before replying, because I had assumed the opposite.

Receptor desensitisation came up in a thread eighteen months ago and was answered well. I cannot find it, which is itself the problem, so here is the reconstruction.

Receptor occupancy required for a clinical effect is not the same as full occupancy, and dose-response curves flattening at the top is what you would expect from that.

Worth checking against a second source before it gets quoted onward.

Amylin signalling reaches satiety through a distinct receptor complex, which is the mechanistic basis for expecting an amylin analogue and an incretin agonist to add rather than overlap.

Happy to expand any of that if it is the useful part.

Signalling through cyclic AMP is the canonical pathway and is not the only one. Beta-arrestin recruitment differs between ligands and its clinical significance here is unestablished.

I would want a second opinion before relying on that.

Agreed, and I will stop repeating the version of this I had been repeating.

Taking post #34 at face value and following it one step further.

Checked the receptor desensitisation claim against the primary source this morning. It survives, with a narrower scope than the version quoted here. Posting the narrower scope.

Receptor distribution explains the side-effect profile better than anything else. GLP-1 receptors in the gastrointestinal tract and the area postrema account for most of what people report.

Someone will know this better than I do and I hope they say so.

The arithmetic in post #38 is right; the assumption feeding it is the part to check.

Nothing in receptor biology tells you what is in the vial, which is worth remembering when a mechanistic thread starts being used to justify a sourcing decision.

This is where my knowledge stops and I would rather mark the edge than blur it.

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.

I am describing what is, rather than arguing for what should be.

Worth separating two things that post #37 runs together.

Pharmacological class effects: all GLP-1 agonists slow gastric emptying and suppress appetite. Those are class effects, not unique to one compound. Effects that differ between compounds are usually about potency or receptor selectivity.

This follows post #41 rather than contradicting it.

The number people quote for receptor desensitisation is a central estimate presented without its interval, and the interval is wide enough that the estimate is nearly uninformative on its own.

Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.

None of the above is medical advice and I am not qualified to give any.

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.

If anyone can point at the primary source I would be grateful.